Degradation of Bruton&#39;s tyrosine kinase (BTK) by conjugation of BTK inhibitors with E3 ligase ligand and methods of use

ABSTRACT

The present application provides bifunctional compounds of Formula (X): 
                         
or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, which act as protein degradation inducing moieties for Bruton&#39;s tyrosine kinase (BTK). The present application also relates to methods for the targeted degradation of BTK through the use of the bifunctional compounds that link a ubiquitin ligase-binding moiety to a ligand that is capable of binding to BTK which can be utilized in the treatment of disorders modulated by BTK.

RELATED APPLICATIONS

This application is a U.S. National Phase application, filed under 35U.S.C. § 371, of International Application No. PCT/US2017/063027, filedon Nov. 22, 2017, which claims priority to, and the benefit of, U.S.Application No. 62/425,211, filed on Nov. 22, 2016, the entire contentsof each of which are incorporated herein by reference.

BACKGROUND

Ubiquitin-Proteasome Pathway (UPP) is a critical pathway that regulatesproteins and degrades misfolded or abnormal proteins. UPP is central tomultiple cellular processes, and if defective or imbalanced, leads topathogenesis of a variety of diseases. The covalent attachment ofubiquitin to specific protein substrates is achieved through the actionof E3 ubiquitin ligases. These ligases comprise over 500 differentproteins and are categorized into multiple classes defined by thestructural element of their E3 functional activity. For example,cereblon (CRBN) interacts with damaged DNA binding protein 1 and formsan E3 ubiquitin ligase complex with Cullin 4 in which the proteinsrecognized by CRBN are ubiquitinated and degraded by proteasomes.Various immunomodulatory drugs (IMiDs), e.g., thalidomide andlenalidomide, binds to CRBN and modulates CRBN's role in theubiquitination and degradation of protein factors involved inmaintaining regular cellular function.

Bifunctional compounds composed of a target protein-binding moiety andan E3 ubiquitin ligase-binding moiety have been shown to induceproteasome-mediated degradation of selected proteins. These drug-likemolecules offer the possibility of temporal control over proteinexpression, and could be useful as biochemical reagents for thetreatment of diseases.

Bruton's tyrosine kinase (BTK) is a member of the Tec family of tyrosinekinases and a key signaling enzyme expressed in B-cells and myeloidcells. BTK plays an essential role in the B-cell signaling pathwaylinking cell surface B-cell receptor (BCR) stimulation to downstreamintracellular responses, and is a key regulator of B-cell development,activation, signaling, and survival. Moreover, BTK plays a role in anumber of other hematopoietic cell signaling pathways, including IgEreceptor signaling in Mast cells, Toll like receptor (TLR) and cytokinereceptor-mediated TNF-α production in macrophages, inhibition ofFas/APO-1 apoptotic signaling in B-lineage lymphoid cells, andcollagen-stimulated platelet aggregation.

Inhibition of BTK has been shown to affect cancer development (e.g., Bcell malignancies) and cell viability, and improve autoimmune diseases(e.g., rheumatoid arthritis and lupus). Compounds which inhibit BTK viaalternative strategies, such as through degradation of BTK, have thepotential to be more potent than known inhibitors of BTK and are needed.The present application addresses the need.

SUMMARY

The present application relates to novel bifunctional compounds, whichfunction to recruit targeted proteins to E3 ubiquitin ligase fordegradation, and methods of preparation and uses thereof. Thebifunctional compound is of Formula X:

wherein:

the Targeting Ligand is capable of binding to a targeted protein, suchas a protein kinase (e.g., BTK);

the Linker is a group that covalently binds to the Targeting Ligand andthe Degron; and

the Degron is capable of binding to a ubiquitin ligase, such as an E3ubiquitin ligase (e.g., cereblon).

The present application also relates to targeted degradation of proteinsthrough the use of bifunctional compounds, including bifunctionalcompounds that link an E3 ubiquitin ligase-binding moiety to a ligandthat binds the targeted proteins.

The present application also relates to a bifunctional compound ofFormula I, II, or III:

or an enantiomer, diastereomer, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein:

R₁, R₂, R_(3b), R₄, R₅, R₆, R₇, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₉, R₂₀, R₂₁,R₂₂, R₂₃, X₁, X₂, Y₂, Y₃, Y₄, Z, A, B, n1, n2, n3, n4, o1, o2, s1, s2,s3, s4, q1, q2, and q3 are each as defined herein;

the Linker is a group that covalently binds to X₂ in Formula (I),

in Formula (II), or Z in Formula (III) and the Degron;

the Degron is capable of binding to a ubiquitin ligase, such as an E3ubiquitin ligase (i.e., cereblon); and

the Targeting Ligand is capable of binding to a targeted protein, suchas BTK.

The present application further relates to a Degron of Formula D1 or D2:

or an enantiomer, diastereomer, or stereoisomer thereof, wherein Y, Z₃,R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, v, q, and q′ are each as defined herein,and the Degron covalently binds to a Linker via

The present application further relates to a Linker of Formula L1 or L2:

or an enantiomer, diastereomer, or stereoisomer thereof, wherein p1, p2,p3, p4, p4′, p5, p6, W, W₁, W₂, W₃, Q₁, Q₂, Z₁, and Z₂ are each asdefined herein, the Linker is covalently bonded to a Degron via the

next to Q₁ or Q₂, and covalently bonded to a Targeting Ligand via the

next to Z₁ or Z₂.

The present application also relates to a pharmaceutical compositioncomprising a therapeutically effective amount of a bifunctional compoundof the application, or an enantiomer, diastereomer, or stereoisomer, orpharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

Another aspect of the present application relates to a method ofinhibiting BTK. The method comprises administering to a subject in needthereof an effective amount of a bifunctional compound of theapplication, or an enantiomer, diastereomer, or stereoisomer, orpharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition of the application.

Another aspect of the present application relates to a method ofmodulating (e.g., decreasing) the amount of BTK. The method comprisesadministering to a subject in need thereof a therapeutically effectiveamount of a bifunctional compound of the application, or an enantiomer,diastereomer, or stereoisomer, or pharmaceutically acceptable saltthereof, or a pharmaceutical composition of the application.

Another aspect of the present application relates to a method oftreating or preventing a disease (e.g., a disease in which BTK plays arole). The method comprises administering to a subject in need thereofan effective amount of a bifunctional compound of the application, or anenantiomer, diastereomer, or stereoisomer, or pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition of theapplication. In one aspect, the disease is BTK mediated disorder. In oneaspect, the disease is a proliferative disease (e.g., a proliferativedisease in which BTK plays a role).

Another aspect of the present application relates to a method oftreating or preventing cancer in a subject, wherein the cancer cellcomprises an activated BTK or wherein the subject is identified as beingin need of BTK inhibition for the treatment or prevention of cancer. Themethod comprises administering to the subject an effective amount of abifunctional compound of the application, or an enantiomer,diastereomer, or stereoisomer, or pharmaceutically acceptable thereof,or a pharmaceutical composition of the application.

Another aspect of the present application relates to a kit comprising abifunctional compound capable of inhibiting BTK activity, selected froma bifunctional compound of the application, or an enantiomer,diastereomer, or stereoisomer, or pharmaceutically acceptable saltthereof.

Another aspect of the present application relates to a kit comprising abifunctional compound capable of modulating (e.g., decreasing) theamount of BTK, selected from a bifunctional compound of the application,or an enantiomer, diastereomer, or stereoisomer, or pharmaceuticallyacceptable salt thereof.

Another aspect of the present application relates to use of abifunctional compound of the application, or an enantiomer,diastereomer, or stereoisomer, or pharmaceutically acceptable saltthereof, or a pharmaceutical composition of the application, in themanufacture of a medicament for inhibiting BTK or for modulating (e.g.,decreasing) the amount of BTK.

Another aspect of the present application relates to use of abifunctional compound of the application, or an enantiomer,diastereomer, or stereoisomer, or pharmaceutically acceptable saltthereof, or a pharmaceutical composition of the application, in themanufacture of a medicament for treating or preventing a disease (e.g.,a disease in which BTK plays a role). In one aspect, the disease is aBTK mediated disorder. In one aspect, the disease is a proliferativedisease (e.g., a proliferative disease in which BTK plays a role).

Another aspect of the present application relates to use of abifunctional compound of the application, or an enantiomer,diastereomer, or stereoisomer, or pharmaceutically acceptable saltthereof, or a pharmaceutical composition of the application, in themanufacture of a medicament for treating or preventing cancer in asubject, wherein the cancer cell comprises an activated BTK or whereinthe subject is identified as being in need of BTK inhibition for thetreatment or prevention of cancer.

Another aspect of the present application relates to a bifunctionalcompound of the application, or an enantiomer, diastereomer, orstereoisomer, or pharmaceutically acceptable salt thereof, or apharmaceutical composition of the application, for inhibiting BTK ormodulating (e.g., decreasing) the amount of BTK.

Another aspect of the present application relates to a bifunctionalcompound of the application, or an enantiomer, diastereomer, orstereoisomer, or pharmaceutically acceptable salt thereof, or apharmaceutical composition of the application, for treating orpreventing a disease (e.g., a disease in which BTK plays a role). In oneaspect, the disease is BTK mediated disorder. In one aspect, the diseaseis a proliferative disease (e.g., a proliferative disease in which BTKplays a role).

Another aspect of the present application relates to a bifunctionalcompound of the application, or an enantiomer, diastereomer, orstereoisomer, or pharmaceutically acceptable salt thereof, or apharmaceutical composition of the application, for treating orpreventing cancer in a subject, wherein the cancer cell comprises anactivated BTK or wherein the subject is identified as being in need ofBTK inhibition for the treatment or prevention of cancer.

The present application provides inhibitors of BTK that are therapeuticagents in the treatment or prevention of diseases such as cancer andmetastasis.

The present application further provides compounds and compositions withan improved efficacy and/or safety profile relative to known BTKinhibitors. The present application also provides agents with novelmechanisms of action toward BTK proteins in the treatment of varioustypes of diseases including cancer and metastasis.

The compounds and methods of the present application address unmet needsin the treatment of diseases or disorders in which pathogenic oroncogenic endogenous proteins (e.g., BTK) play a role, such as cancer.

The details of the disclosure are set forth in the accompanyingdescription below. Although methods and materials similar or equivalentto those described herein can be used in the practice or testing of thepresent application, illustrative methods and materials are nowdescribed. In the case of conflict, the present specification, includingdefinitions, will control. In addition, the materials, methods, andexamples are illustrative only and are not intended to be limiting.Other features, objects, and advantages of the disclosure will beapparent from the description and from the claims. In the specificationand the appended claims, the singular forms also include the pluralunless the context clearly dictates otherwise. Unless defined otherwise,all technical and scientific terms used herein have the same meaning ascommonly understood by one of ordinary skill in the art to which thisdisclosure belongs.

The contents of all references (including literature references, issuedpatents, published patent applications, and co-pending patentapplications) cited throughout this application are hereby expresslyincorporated herein in their entireties by reference. The referencescited herein are not admitted to be prior art to the application.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a Western blot showing the levels of BTK and GAPDH in K562cells treated for 12 hours with DMSO or 200 nM, 1 μM, or 5 μM ofCompound I-1 or Compound I-2. FIG. 1B is a Western blot showing thelevels of BTK and GAPDH in K562 cells treated for 12 hours with DMSO or200 nM, 1 μM, or 5 μM of Compound I-3, Compound I-4, or Compound I-5.

FIG. 2 is a Western blot showing the levels of BTK, Aurora A, andα-tubulin in Molm14 cells treated for 4 hours with DMSO or 40 nM, 200nM, or 1 μM of Compound I-3.

DETAILED DESCRIPTION

Compounds of the Application

The present application relates to bifunctional compounds having utilityas modulators of ubiquitination and proteosomal degradation of targetedproteins, especially compounds comprising a moiety capable of binding toa polypeptide or a protein that is degraded and/or otherwise inhibitedby the bifunctional compounds of the present application. In particular,the present application is directed to compounds which contain a moiety,e.g., a small molecule moiety (i.e., having a molecular weight of below2,000, 1,000, 500, or 200 Daltons), such as a thalidomide-like moiety,which is capable of binding to an E3 ubiquitin ligase, such as cereblon,and a ligand that is capable of binding to a target protein, in such away that the target protein is placed in proximity to the ubiquitinligase to effect degradation (and/or inhibition) of that protein.

In one embodiment, the present application provides a bifunctionalcompound of Formula X:

wherein:

the Targeting Ligand is capable of binding to a targeted protein, suchas BTK;

the Linker is a group that covalently binds to the Targeting Ligand andthe Degron; and

the Degron is capable of binding to a ubiquitin ligase, such as an E3ubiquitin ligase (e.g., cereblon).

In one embodiment, the present application provides a compound ofFormula I:

or an enantiomer, diastereomer, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein:

R₁, R₂, R_(3b), R₄, X₁, X₂, n1, n2, n3, and n4 are each as definedherein;

the Linker is a group that covalently binds to X₂ and the Degron;

the Degron is capable of binding to a ubiquitin ligase, such as an E3ubiquitin ligase (e.g., cereblon); and

the Targeting Ligand is capable of binding to a targeted protein, suchas BTK.

In one embodiment, the present application provides a compound ofFormula II:

or an enantiomer, diastereomer, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein:

R₅, R₆, R₇, A, B, Y₂, Y₃, o1, and o2 are each as defined herein;

the Linker is a group that covalently binds to and the Degron;

the Degron is capable of binding to a ubiquitin ligase, such as an E3ubiquitin ligase (e.g., cereblon); and

the Targeting Ligand is capable of binding to a targeted protein, suchas BTK.

In one embodiment, the present application provides a compound ofFormula III:

or an enantiomer, diastereomer, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein:

R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, Z, s1, s2, s3, and s4 are each as definedherein;

the Linker is a group that covalently binds to Z and the Degron;

the Degron is capable of binding to a ubiquitin ligase, such as an E3ubiquitin ligase (e.g., cereblon); and

the Targeting Ligand is capable of binding to a targeted protein, suchas BTK.

The present application further relates to a Degron of Formula D1:

or an enantiomer, diastereomer, or stereoisomer thereof, wherein Y, Z₃,R₂₈, R₂₉, R₃₀, R₃₁, q, and v are each as defined herein, and the Degroncovalently binds to a Linker via

The present application further relates to a Degron of Formula D2:

or an enantiomer, diastereomer, or stereoisomer thereof, wherein R₃₂,R₃₃, and q′ are each as defined herein, and the Degron covalently bindsto a Linker via

The present application further relates to a Linker of Formula L1:

or an enantiomer, diastereomer, or stereoisomer thereof, wherein p1, p2,p3, W, Q₁, and Z₁ are each as defined herein, the Linker is covalentlybonded to a Degron via the

next to Q₁, and covalently bonded to a Targeting Ligand via the

next to Z₁.

The present application further relates to a Linker of Formula L2:

or an enantiomer, diastereomer, or stereoisomer thereof, wherein p4,p4′, p5, p6, W₁, W₂, W₃, Q₂, and Z₂ are each as defined herein, theLinker is covalently bonded to a Degron via the

next to Q₂, and covalently bonded to the Targeting Ligand via the

next to Z₂.Targeting Ligand

Targeting Ligand (TL) (or target protein moiety or target protein ligandor ligand) is a small molecule which is capable of binding to a targetprotein of interest, such BTK.

In one embodiment, a Targeting Ligand is a compound of Formula TL-I:

or an enantiomer, diastereomer, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein:

X₁ is O or NR_(3a);

X₂ is O or

each R₁ is independently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄)alkoxy, (C₁-C₄) haloalkoxy, halogen, OH, or NH₂;

each R₂ is independently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄)alkoxy, (C₁-C₄) haloalkoxy, halogen, CN, OH, or NH₂;

R_(3a) and R_(3b) are each independently H, (C₁-C₄) alkyl, or (C₁-C₄)haloalkyl;

each R₄ is independently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄)alkoxy, (C₁-C₄) haloalkoxy, halogen, OH, or NH₂;

n1 and n2 are each independently 0, 1, or 2;

n3 is 0, 1, 2, 3 or 4; and

n4 is 1, 2, 3 or 4,

wherein the Targeting Ligand is bonded to the Linker via the

next to X₂.

In some embodiments, X₁ is O. In another embodiment, X₁ is NR_(3a).

In some embodiments, R_(3a) is H, (C₁-C₃) alkyl, or (C₁-C₃) haloalkyl.In other embodiments, R_(3a) is H or (C₁-C₄) alkyl. In otherembodiments, R_(3a) is H, methyl, ethyl, n-propyl, or i-propyl. In otherembodiments, R_(3a) is H, methyl or ethyl. In other embodiments, R_(3a)is (C₁-C₄) alkyl. In other embodiments, R_(3a) is methyl, ethyl,n-propyl, or i-propyl. In other embodiments, R_(3a) is methyl or ethyl.In other embodiments, R_(3a) is (C₁-C₄) alkyl or (C₁-C₄) haloalkyl. Inother embodiments, R_(3a) is H.

In some embodiments, X₂ is O. In another embodiment, X₂ is

In some embodiments, each R₁ is independently (C₁-C₃) alkyl, (C₁-C₃)haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, halogen, OH, or NH₂. Inother embodiments, each R₁ is independently (C₁-C₃) alkyl, (C₁-C₃)haloalkyl, (C₁-C₃) alkoxy, or (C₁-C₃) haloalkoxy. In other embodiments,each R₁ is independently halogen, OH, or NH₂. In other embodiments, eachR₁ is independently (C₁-C₃) alkoxy or (C₁-C₃) haloalkoxy. In otherembodiments, each R₁ is independently (C₁-C₃) alkoxy. In otherembodiments, each R₁ is independently methoxy, ethoxy, n-propoxy, ori-propoxy. In other embodiments, each R₁ is independently methoxy orethoxy. In other embodiments, at least one R₁ is methoxy.

In some embodiments, each R₂ is independently (C₁-C₃) alkyl, (C₁-C₃)haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, halogen, CN, OH, or NH₂.In other embodiments, each R₂ is independently (C₁-C₃) alkyl, (C₁-C₃)haloalkyl, (C₁-C₃) alkoxy, or (C₁-C₃) haloalkoxy. In other embodiments,each R₂ is independently halogen, CN, OH, or NH₂. In other embodiments,each R₂ is independently CN, OH, or NH₂. In other embodiments, at leastone R₂ is CN.

In some embodiments, R_(3b) is H, (C₁-C₃) alkyl, or (C₁-C₃) haloalkyl.In other embodiments, R_(3b) is H or (C₁-C₄) alkyl. In otherembodiments, R_(3b) is H, methyl, ethyl, n-propyl, or i-propyl. In otherembodiments, R_(3b) is H, methyl or ethyl. In other embodiments, R_(3b)is (C₁-C₄) alkyl. In other embodiments, R_(3b) is methyl, ethyl,n-propyl, or i-propyl. In other embodiments, R_(3b) is methyl or ethyl.In other embodiments, R_(3b) is (C₁-C₄) alkyl or (C₁-C₄) haloalkyl. Inother embodiments, R_(3b) is H.

In some embodiments, each R₄ is independently (C₁-C₃) alkyl, (C₁-C₃)haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, halogen, OH, or NH₂. Inother embodiments, each R₄ is independently (C₁-C₃) alkyl, (C₁-C₃)haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, or halogen. In otherembodiments, each R₄ is independently halogen, OH, or NH₂. In otherembodiments, each R₄ is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl,(C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, or halogen. In other embodiments,each R₄ is independently (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, halogen,OH, or NH₂. In other embodiments, each R₄ is independently (C₁-C₃)alkoxy, (C₁-C₃) haloalkoxy, or halogen. In other embodiments, each R₄ isindependently (C₁-C₃) alkoxy or halogen. In other embodiments, each R₄is independently methoxy, ethoxy, n-propoxy, i-propoxy, F, or Cl. Inother embodiments, each R₄ is independently methoxy, ethoxy, F, or Cl.In other embodiments, each R₄ is independently methoxy or C₁. In otherembodiments, at least one R₄ is methoxy and at least one R₄ is C₁.

In some embodiments, n1 is 0. In other embodiments, n1 is 1. In otherembodiments, n1 is 2. In other embodiments, n1 is 0 or 1. In otherembodiments, n1 is 1 or 2.

In some embodiments, n2 is 0. In other embodiments, n2 is 1. In otherembodiments, n2 is 2. In other embodiments, n2 is 0 or 1. In otherembodiments, n2 is 1 or 2.

In some embodiments, n3 is 0. In other embodiments, n3 is 1. In otherembodiments, n3 is 2. In other embodiments, n3 is 3. In otherembodiments, n3 is 4. In other embodiments, n3 is 0 or 1. In otherembodiments, n3 is 1 or 2. In other embodiments, n3 is 0, 1 or 2. Inother embodiments, n3 is 1, 2 or 3. In other embodiments, n3 is 2, 3 or4. In other embodiments, n3 is 1, 2, 3, or 4. In other embodiments, n3is 0, 1, 2 or 3.

In some embodiments, n4 is 1. In other embodiments, n4 is 2. In otherembodiments, n4 is 3. In other embodiments, n4 is 4. In otherembodiments, n4 is 1 or 2. In other embodiments, n4 is 3 or 4. In otherembodiments, n4 is 1, 2 or 3. In other embodiments, n4 is 2, 3 or 4.

Any of the groups described herein for any of X₁, X₂, R₁, R₂, R_(3a),R_(3b), R₄, n1, n2, n3, and n4 can be combined with any of the groupsdescribed herein for one or more of the remainder of X₁, X₂, R₁, R₂,R_(3a), R_(3b), R₄, n1, n2, n3, and n4, and may further be combined withany of the groups described herein for the Linker.

For a Targeting Ligand of Formula TL-I:

-   -   (1) In one embodiment, X₁ is NR_(3a) and X₂ is O.    -   (2) In one embodiment, X₁ is NR_(3a) and X₂ is

-   -   (3) In one embodiment, X₁ is NR_(3a), X₂ is O, and each R₁ is        independently (C₁-C₄) alkoxy.    -   (4) In one embodiment, X₁ is NR_(3a), X₂ is

and each R₁ is independently (C₁-C₄) alkoxy.

-   -   (5) In one embodiment, X₁ is NR_(3a), X₂ is O, each R₁ is        independently (C₁-C₄) alkoxy, and at least one R₂ is CN.    -   (6) In one embodiment, X₁ is NR_(3a), X₂ is

each R₁ is independently (C₁-C₄) alkoxy, and at least one R₂ is CN.

-   -   (7) In one embodiment, X₁ is NR_(3a), X₂ is O, each R₁ is        independently (C₁-C₄) alkoxy, at least one R₂ is CN, and R_(3b)        is H.    -   (8) In one embodiment, X₁ is NR_(3a), X₂ is

each R₁ is independently (C₁-C₄) alkoxy, at least one R₂ is CN, andR_(3b) is H.

-   -   (9) In one embodiment, X₁ is NR_(3a), X₂ is O, each R₁ is        independently (C₁-C₄) alkoxy, at least one R₂ is CN, R_(3b) is        H, and each R₄ is independently (C₁-C₄) alkoxy or halogen.    -   (10) In one embodiment, X₁ is NR_(3a), X₂ is

each R₁ is independently (C₁-C₄) alkoxy, at least one R₂ is CN, R_(3b)is H, and each R₄ is independently (C₁-C₄) alkoxy or halogen.

-   -   (11) In one embodiment, X₁ is O and X₂ is O.    -   (12) In one embodiment, X₁ is O and X₂ is

-   -   (13) In one embodiment, X₁ is O, X₂ is O, and each R₁ is        independently (C₁-C₄) alkoxy.    -   (14) In one embodiment, X₁ is O, X₂ is

and each R₁ is independently (C₁-C₄) alkoxy.

-   -   (15) In one embodiment, X₁ is O, X₂ is O, each R₁ is        independently (C₁-C₄) alkoxy, and at least one R₂ is CN.    -   (16) In one embodiment, X₁ is O, X₂ is

each R₁ is independently (C₁-C₄) alkoxy, and at least one R₂ is CN.

-   -   (17) In one embodiment, X₁ is O, X₂ is O, each R₁ is        independently (C₁-C₄) alkoxy, at least one R₂ is CN, and R_(3b)        is H.    -   (18) In one embodiment, X₁ is O, X₂ is

each R₁ is independently (C₁-C₄) alkoxy, at least one R₂ is CN, andR_(3b) is H.

-   -   (19) In one embodiment, X₁ is O, X₂ is O, each R₁ is        independently (C₁-C₄) alkoxy, at least one R₂ is CN, R_(3b) is        H, and each R₄ is independently (C₁-C₄) alkoxy or halogen.    -   (20) In one embodiment, X₁ is O, X₂ is

each R₁ is independently (C₁-C₄) alkoxy, at least one R₂ is CN, R_(3b)is H, and each R₄ is independently (C₁-C₄) alkoxy or halogen.

-   -   (21) In one embodiment, each R₁ is independently (C₁-C₄) alkoxy.    -   (22) In one embodiment, each R₁ is independently (C₁-C₄) alkoxy        and at least one R₂ is CN.    -   (23) In one embodiment, X₂ is

and each R₁ is independently (C₁-C₄) alkoxy.

(24) In one embodiment, X₂ is O and each R₁ is independently (C₁-C₄)alkoxy.

-   -   (25) In one embodiment, X₂ is

each R₁ is independently (C₁-C₄) alkoxy, and at least one R₂ is CN.

-   -   (26) In one embodiment, X₂ is O, each R₁ is independently        (C₁-C₄) alkoxy, and at least one R₂ is CN.    -   (27) In one embodiment, X₂ is

each R₁ is independently (C₁-C₄) alkoxy, and R_(3b) is H.

-   -   (28) In one embodiment, X₂ is O, each R₁ is independently        (C₁-C₄) alkoxy, and R_(3b) is H.    -   (29) In one embodiment, X₂ is

each R₁ is independently (C₁-C₄) alkoxy, R_(3b) is H, and each R₄ isindependently (C₁-C₄) alkoxy or halogen.

-   -   (30) In one embodiment, X₂ is O, each R₁ is independently        (C₁-C₄) alkoxy, R_(3b) is H, and each R₄ is independently        (C₁-C₄) alkoxy or halogen.    -   (31) In one embodiment, each R₁ is independently (C₁-C₄) alkoxy,        at least one R₂ is CN, and R_(3b) is H.    -   (32) In one embodiment, R₁, R₂, R_(3a), R_(3b), R₄, X₁, and X₂        are each as defined, where applicable, in any one of (1)-(31),        and n1 is 1.    -   (33) In one embodiment, R₁, R₂, R_(3a), R_(3b), R₄, X₁, and X₂        are each as defined, where applicable, in any one of (1)-(31),        and n2 is 1.    -   (34) In one embodiment, R₁, R₂, R_(3a), R_(3b), R₄, X₁, and X₂        are each as defined, where applicable, in any one of (1)-(31),        and n3 is 1.    -   (35) In one embodiment, R₁, R₂, R_(3a), R_(3b), R₄, X₁, and X₂        are each as defined, where applicable, in any one of (1)-(31),        and n3 is 2.    -   (36) In one embodiment, R₁, R₂, R_(3a), R_(3b), R₄, X₁, and X₂        are each as defined, where applicable, in any one of (1)-(31),        and n3 is 3.    -   (37) In one embodiment, R₁, R₂, R_(3a), R_(3b), R₄, X₁, and X₂        are each as defined, where applicable, in any one of (1)-(31),        and n4 is 1.    -   (38) In one embodiment, R₁, R₂, R_(3a), R_(3b), R₄, X₁, and X₂        are each as defined, where applicable, in any one of (1)-(31),        and n4 is 2.    -   (39) In one embodiment, R₁, R₂, R_(3a), R_(3b), R₄, X₁, and X₂        are each as defined, where applicable, in any one of (1)-(31),        and n4 is 3.    -   (40) In one embodiment, R₁, R₂, R_(3a), R_(3b), R₄, X₁, and X₂        are each as defined, where applicable, in any one of (1)-(31),        n1 is 1, and n2 is 1.    -   (41) In one embodiment, R₁, R₂, R_(3a), R_(3b), R₄, X₁, and X₂        are each as defined, where applicable, in any one of (1)-(31),        n1 is 1, n2 is 1, and n3 is 3.    -   (42) In one embodiment, R₁, R₂, R_(3a), R_(3b), R₄, X₁, and X₂        are each as defined, where applicable, in any one of (1)-(31),        n1 is 1, n2 is 1, n3 is 3, and n4 is 3.

In one embodiment, the compound of Formula TL-I is of Formula TL-Ia:

wherein X₂, R₁, R₄, n3, and n4 are each as defined above in FormulaTL-I.

For a Targeting Ligand of Formula TL-Ia:

-   -   (1) In one embodiment, R₁ is (C₁-C₄) alkoxy and each R₄ is        independently (C₁-C₄) alkoxy or halogen.    -   (2) In one embodiment, R₁ is (C₁-C₃) alkoxy and each R₄ is        independently (C₁-C₃) alkoxy or halogen.    -   (3) In one embodiment, R₁ is methoxy and each R₄ is        independently methoxy, F or Cl.    -   (4) In one embodiment, R₁ is methoxy and each R₄ is        independently methoxy or C₁.    -   (5) In one embodiment, X₂ is O.    -   (6) In one embodiment, X₂ is

-   -   (7) In one embodiment, R₁ is (C₁-C₄) alkoxy, each R₄ is        independently (C₁-C₄) alkoxy or halogen, and X₂ is O.    -   (8) In one embodiment, R₁ is (C₁-C₄) alkoxy, each R₄ is        independently (C₁-C₄) alkoxy or halogen, and X₂ is

-   -   (9) In one embodiment, R₁, R₄, and X₂ are each as defined, where        applicable, in any one of (1)-(8), and n4 is 3.    -   (10) In one embodiment, R₁, R₄, and X₂ are each as defined,        where applicable, in any one of (1)-(8), and n3 is 3.    -   (11) In one embodiment, R₁, R₄, and X₂ are each as defined,        where applicable, in any one of (1)-(8), n3 is 3, and n4 is 3.    -   (12) In one embodiment, X₂ is O and n4 is 3.    -   (13) In one embodiment, X₂ is

and n4 is 3.

-   -   (14) In one embodiment, X₂ is O and n3 is 3.    -   (15) In one embodiment, X₂ is

and n3 is 3.

X₂, R₁, R₄, n3, and n4 can each be selected from any of the groups andcombined as described above in Formula TL-I or TL-Ia.

In another embodiment, the compound of Formula TL-I is of Formula TL-Ib:

wherein X₂, R₁, and n4 are each as defined above in Formula TL-I.

For a Targeting Ligand of Formula TL-Ib:

-   -   (1) In one embodiment, R₁ is (C₁-C₃) alkoxy.    -   (2) In one embodiment, R₁ is methoxy.    -   (3) In one embodiment, R₁ is (C₁-C₃) alkoxy, and n4 is 3.    -   (4) In one embodiment, R₁ is methoxy and n4 is 1, 2, or 3.    -   (5) In one embodiment, R₁ is (C₁-C₃) alkoxy and X₂ is O.    -   (6) In one embodiment, R₁ is (C₁-C₃) alkoxy and X₂ is

-   -   (7) In one embodiment, R₁ is methoxy and X₂ is O.    -   (8) In one embodiment, R₁ is methoxy and X₂ is

-   -   (9) In one embodiment, R₁ is (C₁-C₃) alkoxy, X₂ is O, and n4 is        3.    -   (10) In one embodiment, R₁ is (C₁-C₃) alkoxy, X₂ is

and n4 is 3.

-   -   (11) In one embodiment, R₁ is methoxy, X₂ is O, and n4 is 3.    -   (12) In one embodiment, R₁ is methoxy, X₂ is

and n4 is 3.

R₁, X₂, and n4 can each be selected from any of the groups and combinedas described above in Formula TL-I or TL-Ib.

In one embodiment, a Targeting Ligand is a compound of Formula TL-II:

or an enantiomer, diastereomer, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein:

A is phenyl or 5- or 6-membered heteroaryl containing 1 or 2 heteroatomsselected from N and S, wherein the phenyl or heteroaryl is optionallysubstituted with 1 to 3 R₈;

B is phenyl or 5- or 6-membered heteroaryl containing 1 or 2 heteroatomsselected from N and S, wherein the phenyl or heteroaryl is optionallysubstituted with 1 to 3 R₉;

Y₂ is NR_(10a) or O;

Y₃ is C(O)NR_(10b) or NR_(10b)C(O);

Y₄ is NR₅′ or, when B is bonded to Y₄, N;

R₅′ is H, (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄)haloalkoxy, or halogen;

each R₅ is independently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄)alkoxy, (C₁-C₄) haloalkoxy, halogen, or oxo;

R₆ is H, (C₁-C₄) alkyl, or (C₁-C₄) haloalkyl;

each R₇ is independently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄)alkoxy, (C₁-C₄) haloalkoxy, (C₁-C₄) hydroxyalkyl, halogen, OH, or NH₂;

each R₈ is independently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄)alkoxy, (C₁-C₄) haloalkoxy, halogen, OH, NH₂, or (C₃-C₆) cycloalkyl; ortwo R₈ together with the atoms to which they are attached form a (C₅-C₇)cycloalkyl ring; or R₈ and R_(10b) together with the atoms to which theyare attached form a 5- or 6-membered heterocycloalkyl or heteroarylcontaining 1 or 2 heteroatoms selected from N, O, and S and optionallysubstituted with 1 to 3 R₁₁;

each R₉ is independently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄)alkoxy, (C₁-C₄) haloalkoxy, or halogen;

R_(10a) and R_(10b) are each independently H, (C₁-C₄) alkyl, or (C₁-C₄)haloalkyl; or R₈ and R_(10b) together with the atoms to which they areattached form a 5- or 6-membered heterocycloalkyl or heteroarylcontaining 1 or 2 heteroatoms selected from N, O, and S and optionallysubstituted with 1 to 3 R₁₁;

each R₁₁ is independently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄)alkoxy, (C₁-C₄) haloalkoxy, halogen, OH, or NH₂; and

o1 and o2 are each independently 0, 1, 2, or 3,

wherein the Targeting Ligand is bonded to the Linker via the

next to

In some embodiments, A is phenyl optionally substituted with 1 to 3 R₈.In other embodiments, A is 5- or 6-membered heteroaryl containing 1 or 2heteroatoms selected from N and S optionally substituted with 1 to 3 R₈.In other embodiments, A is phenyl or thiophenyl wherein each isoptionally substituted with 1 to 3 R₈. In other embodiments, A is phenylor thiophenyl wherein each is substituted with 1 to 3 R₈. In otherembodiments, A is phenyl or thiophenyl wherein each is optionallysubstituted with 1 to 2 R₈. In other embodiments, A is phenyl orthiophenyl wherein each is substituted with 1 to 2 R₈. In otherembodiments, A is phenyl substituted with 1 to 2 R₈. In otherembodiments, A is phenyl substituted with 3 R₈. In other embodiments, Ais thiophenyl substituted with 1 to 2 R₈.

In some embodiments, B is phenyl optionally substituted with 1 to 3 R₉.In other embodiments, B is 5- or 6-membered heteroaryl containing 1 or 2heteroatoms selected from N and S, optionally substituted with 1 to 3R₉. In other embodiments, B is 5-membered heteroaryl containing 1 or 2heteroatoms selected from N and S, optionally substituted with 1 to 3R₉. In other embodiments, B is 6-membered heteroaryl containing 1 or 2heteroatoms selected from N and S, optionally substituted with 1 to 3R₉. In other embodiments, B is 5- or 6-membered heteroaryl containing 1or 2 heteroatoms selected from N and S. In other embodiments, B is5-membered heteroaryl containing 1 or 2 heteroatoms selected from N andS. In other embodiments, B is 6-membered heteroaryl containing 1 or 2heteroatoms selected from N and S. In other embodiments, B is pyridinyloptionally substituted with 1 to 3 R₉. In other embodiments, B isphenyl. In other embodiments, B is pyridinyl.

In some embodiments, Y₂ is NR_(10a). In other embodiments, Y₂ is O.

In some embodiments, Y₃ is C(O)NR_(10b). In other embodiments, Y₃ isNR_(10b)C(O).

In some embodiments, Y₄ is NR₅′. In other embodiments, Y₄ is N.

In some embodiments, R₅′ is (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, (C₁-C₃)alkoxy, (C₁-C₃) haloalkoxy, or halogen. In other embodiments, R₅′ is(C₁-C₃) alkyl, (C₁-C₃) haloalkyl, (C₁-C₃) alkoxy, or (C₁-C₃) haloalkoxy.In other embodiments, R₅′ is (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, orhalogen. In other embodiments, R₅′ is (C₁-C₃) alkyl or halogen. In otherembodiments, R₅′ is methyl, ethyl, n-propyl, or i-propyl. In otherembodiments, R₅′ is methyl or ethyl. In other embodiments, R₅′ ismethyl.

In some embodiments, each R₅ is independently (C₁-C₃) alkyl, (C₁-C₃)haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, halogen, or oxo. In otherembodiments, each R₅ is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl,(C₁-C₃) alkoxy, or (C₁-C₃) haloalkoxy. In other embodiments, each R₅ isindependently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, halogen, or oxo. Inother embodiments, each R₅ is independently (C₁-C₃) alkyl, halogen, oroxo. In other embodiments, each R₅ is independently (C₁-C₃) alkyl oroxo. In other embodiments, each R₅ is independently methyl, ethyl,n-propyl, i-propyl, or oxo. In other embodiments, each R₅ isindependently methyl, ethyl, or oxo. In other embodiments, each R₅ isindependently methyl or oxo.

In some embodiments, R₆ is H, (C₁-C₃) alkyl, or (C₁-C₃) haloalkyl. Inother embodiments, R₆ is H or (C₁-C₄) alkyl. In other embodiments, R₆ isH or (C₁-C₃) alkyl. In other embodiments, R₆ is H, methyl, ethyl,n-propyl, or i-propyl. In other embodiments, R₆ is H, methyl, or ethyl.In other embodiments, R₆ is (C₁-C₄) alkyl. In other embodiments, R₆ ismethyl, ethyl, n-propyl, or i-propyl. In other embodiments, R₆ is H. Inother embodiments, R₆ is methyl or ethyl. In other embodiments, R₆ ismethyl.

In some embodiments, each R₇ is independently (C₁-C₃) alkyl, (C₁-C₃)haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, (C₁-C₃) hydroxyalkyl,halogen, OH, or NH₂. In other embodiments, each R₇ is independently(C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy,(C₁-C₄) hydroxyalkyl, halogen, or OH. In other embodiments, each R₇ isindependently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄)haloalkoxy, (C₁-C₄) hydroxyalkyl, or OH. In other embodiments, each R₇is independently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) hydroxyalkyl,halogen, or OH. In other embodiments, each R₇ is independently (C₁-C₄)alkyl, (C₁-C₄) alkoxy, (C₁-C₄) hydroxyalkyl, or OH. In otherembodiments, each R₇ is independently (C₁-C₄) alkyl, (C₁-C₄)hydroxyalkyl, or OH. In other embodiments, each R₇ is independently(C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl. In other embodiments, each R₇ isindependently (C₁-C₃) alkyl or (C₁-C₃) hydroxyalkyl. In otherembodiments, each R₇ is independently (C₁-C₃) alkyl. In otherembodiments, each R₇ is independently (C₁-C₃) hydroxyalkyl. In otherembodiments, each R₇ is independently methyl, ethyl, n-propyl, i-propyl,or (C₁-C₃) hydroxyalkyl. In other embodiments, each R₇ is independentlymethyl, ethyl, n-propyl, i-propyl, CH₂OH, CH₂CH₂OH, CH₂CH₂CH₂OH,CH(OH)CH₃, CH(OH)CH₂CH₃, or CH₂CH(OH)CH₃. In other embodiments, each R₇is independently methyl, ethyl, CH₂OH, CH₂CH₂OH, or CH(OH)CH₃. In otherembodiments, each R₇ is independently methyl, ethyl, CH₂OH, or CH₂CH₂OH.In other embodiments, each R₇ is independently methyl or CH₂OH.

In some embodiments, each R₈ is independently (C₁-C₃) alkyl, (C₁-C₃)haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, halogen, OH, NH₂, or(C₃-C₆) cycloalkyl. In other embodiments, each R₈ is independently(C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, orhalogen. In other embodiments, each R₈ is independently (C₁-C₄) alkyl,(C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, halogen, or(C₃-C₆) cycloalkyl. In other embodiments, each R₈ is independently(C₁-C₄) alkyl, (C₁-C₄) haloalkyl, halogen, or (C₃-C₆) cycloalkyl. Inother embodiments, each R₈ is independently (C₁-C₄) alkyl, halogen, or(C₃-C₆) cycloalkyl. In other embodiments, each R₈ is independentlymethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, F, Cl,cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In otherembodiments, each R₈ is independently n-propyl, i-propyl, n-butyl,i-butyl, t-butyl, F, Cl, cyclopropyl, cyclobutyl, or cyclopentyl. Inother embodiments, each R₈ is independently i-propyl, i-butyl, t-butyl,F, or cyclopropyl. In other embodiments, each R₈ is independentlyi-propyl, t-butyl, F, or cyclopropyl. In other embodiments, each R₈ isindependently t-butyl, F, or cyclopropyl. In other embodiments, at leastone R₈ is t-butyl. In other embodiments, at least one R₈ is F. In otherembodiments, at least one R₈ is cyclopropyl. In other embodiments, atleast one R₈ is F, and at least one R₈ is cyclopropyl.

In some embodiments, two R₈ together with the atoms to which they areattached form a (C₅-C₇) cycloalkyl ring. In some embodiments, two R₈together with the atoms to which they are attached form a cyclopentylring. In some embodiments, two R₈ together with the atoms to which theyare attached form a cyclohexyl ring.

In some embodiments, each R₉ is independently (C₁-C₃) alkyl, (C₁-C₃)haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, or halogen. In otherembodiments, each R₉ is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl,or halogen. In other embodiments, each R₉ is independently (C₁-C₃)alkoxy, (C₁-C₃) haloalkoxy, or halogen. In other embodiments, each R₉ isindependently (C₁-C₃) alkyl, (C₁-C₃) alkoxy, or halogen. In otherembodiments, each R₉ is independently (C₁-C₃) alkyl, or halogen. Inother embodiments, each R₉ is independently methyl, ethyl, n-propyl,i-propyl, F or Cl.

In some embodiments, R₈ and R_(10b) together with the atoms to whichthey are attached form a 5-membered heterocycloalkyl or heteroarylcontaining 1 or 2 heteroatoms selected from N, O, and S and optionallysubstituted with 1 to 3 R₁₁. In other embodiments, R₈ and R_(10b)together with the atoms to which they are attached form a 6-memberedheterocycloalkyl or heteroaryl containing 1 or 2 heteroatoms selectedfrom N, O, and S and optionally substituted with 1 to 3 R₁₁. In otherembodiments, R₈ and R_(10b) together with the atoms to which they areattached form a 5- or 6-membered heterocycloalkyl containing 1 or 2heteroatoms selected from N, O, and S and optionally substituted with 1to 3 R₁₁. In other embodiments, R₈ and R_(10b) together with the atomsto which they are attached form a 5- or 6-membered heteroaryl containing1 or 2 heteroatoms selected from N, O, and S and optionally substitutedwith 1 to 3 R₁₁.

In other embodiments, R₈ and R_(10b) together with the atoms to whichthey are attached form a 5-membered heterocycloalkyl containing 1 or 2heteroatoms selected from N, O, and S and optionally substituted with 1to 3 R₁₁. In other embodiments, R₈ and R_(10b) together with the atomsto which they are attached form a 6-membered heterocycloalkyl containing1 or 2 heteroatoms selected from N, O, and S and optionally substitutedwith 1 to 3 R₁₁. In other embodiments, R₈ and R_(10b) together with theatoms to which they are attached form a 5-membered heteroaryl containing1 or 2 heteroatoms selected from N, O, and S and optionally substitutedwith 1 to 3 R₁₁. In other embodiments, R₈ and R_(10b) together with theatoms to which they are attached form a 6-membered heteroaryl containing1 or 2 heteroatoms selected from N, O, and S and optionally substitutedwith 1 to 3 R₁₁.

In some embodiments, R_(10a) is H, (C₁-C₃) alkyl, or (C₁-C₃) haloalkyl.In other embodiments, R_(10a) is (C₁-C₄) alkyl or (C₁-C₄) haloalkyl. Inother embodiments, R_(10a) is H or (C₁-C₄) alkyl. In other embodiments,R_(10a) is H, methyl, ethyl, n-propyl, or i-propyl. In otherembodiments, R_(10a) is H, methyl or ethyl. In other embodiments,R_(10a) is (C₁-C₄) alkyl. In other embodiments, R_(10a) is methyl,ethyl, n-propyl, or i-propyl. In other embodiments, R_(10a) is methyl orethyl. In other embodiments, R_(10a) is H.

In some embodiments, R_(10b) is H, (C₁-C₃) alkyl, or (C₁-C₃) haloalkyl.In other embodiments, R_(10b) is (C₁-C₄) alkyl or (C₁-C₄) haloalkyl. Inother embodiments, R_(10b) is H or (C₁-C₄) alkyl. In other embodiments,R_(10b) is H, methyl, ethyl, n-propyl, or i-propyl. In otherembodiments, R_(10b) is H, methyl or ethyl. In other embodiments,R_(10b) is (C₁-C₄) alkyl. In other embodiments, R_(10b) is methyl,ethyl, n-propyl, or i-propyl. In other embodiments, R_(10b) is methyl orethyl. In other embodiments, R_(10b) is H.

In some embodiments, each R₁₁ is independently (C₁-C₃) alkyl, (C₁-C₃)haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, halogen, OH, or NH₂. Inother embodiments, each R₁₁ is independently (C₁-C₃) alkyl, (C₁-C₃)haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, or halogen. In otherembodiments, each R₁₁ is independently halogen, OH, or NH₂. In otherembodiments, each R₁₁ is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl,(C₁-C₃) alkoxy, or (C₁-C₃) haloalkoxy. In other embodiments, each R₁₁ isindependently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, or halogen. In otherembodiments, each R₁₁ is independently methyl, ethyl, n-propyl,i-propyl, F, or Cl.

In some embodiments, o1 is 0. In other embodiments, o1 is 1. In otherembodiments, o1 is 2. In other embodiments, o1 is 3. In otherembodiments, o1 is 0 or 1. In other embodiments, o1 is 1 or 2. In otherembodiments, o1 is 2 or 3. In other embodiments, o1 is 0, 1 or 2. Inother embodiments, o1 is 1, 2, or 3.

In some embodiments, o2 is 0. In other embodiments, o2 is 1. In otherembodiments, o2 is 2. In other embodiments, o2 is 3. In otherembodiments, o2 is 0 or 1. In other embodiments, o2 is 1 or 2. In otherembodiments, o2 is 2 or 3. In other embodiments, o2 is 0, 1 or 2. Inother embodiments, o2 is 1, 2, or 3.

Any of the groups described herein for any of A, B, Y₂, Y₃, Y₄, R₅, R₅′,R₆, R₇, R₈, R₉, R_(10a), R_(10b), R₁₁, o1, and o2 can be combined withany of the groups described herein for one or more of the remainder ofA, B, Y₂, Y₃, Y₄, R₅, R₅′, R₆, R₇, R₈, R₉, R_(10a), R_(10b), R₁₁, o1,and o2, and may further be combined with any of the groups describedherein for the Linker.

For a Targeting Ligand of Formula TL-II:

-   -   (1) In one embodiment, B is phenyl and Y₂ is NR_(10a).    -   (2) In one embodiment, B is phenyl, Y₂ is NR_(10a), and R₆ is        (C₁-C₄) alkyl.    -   (3) In one embodiment, B is phenyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, and each R₇ is independently (C₁-C₄) alkyl or        (C₁-C₄) hydroxyalkyl.    -   (4) In one embodiment, B is phenyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, and each R₇ is independently (C₁-C₄) alkyl.    -   (5) In one embodiment, B is phenyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, and each R₇ is independently (C₁-C₄)        hydroxyalkyl.    -   (6) In one embodiment, B is phenyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄)        hydroxyalkyl, and Y₃ is C(O)NR_(10b).    -   (7) In one embodiment, B is phenyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and Y₃ is        C(O)NR_(10b).    -   (8) In one embodiment, B is phenyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl,        and Y₃ is C(O)NR_(10b).    -   (9) In one embodiment, B is phenyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄)        hydroxyalkyl, Y₃ is C(O)NR_(10b), and each R₈ is independently        (C₁-C₄) alkyl, halogen, or (C₃-C₆) cycloalkyl, or two R₈        together with the atoms to which they are attached form a        (C₅-C₇) cycloalkyl ring.    -   (10) In one embodiment, B is phenyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄)        hydroxyalkyl, Y₃ is C(O)NR_(10b), and each R₈ is independently        (C₁-C₄) alkyl, halogen, or (C₃-C₆) cycloalkyl.    -   (11) In one embodiment, B is phenyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄)        hydroxyalkyl, Y₃ is C(O)NR_(10b), and each R₈ is independently        (C₁-C₄) alkyl.    -   (12) In one embodiment, B is phenyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄)        hydroxyalkyl, Y₃ is C(O)NR_(10b), and each R₈ is independently        halogen or (C₃-C₆) cycloalkyl.    -   (13) In one embodiment, B is phenyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄)        hydroxyalkyl, Y₃ is C(O)NR_(10b), and two R₈ together with the        atoms to which they are attached form a (C₅-C₇) cycloalkyl ring.    -   (14) In one embodiment, B is phenyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, Y₃ is        C(O)NR_(10b), and each R₈ is independently (C₁-C₄) alkyl,        halogen, or (C₃-C₆) cycloalkyl, or two R₈ together with the        atoms to which they are attached form a (C₅-C₇) cycloalkyl ring.    -   (15) In one embodiment, B is phenyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, Y₃ is        C(O)NR_(10b), and each R₈ is independently (C₁-C₄) alkyl,        halogen, or (C₃-C₆) cycloalkyl.    -   (16) In one embodiment, B is phenyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, Y₃ is        C(O)NR_(10b), and each R₈ is independently (C₁-C₄) alkyl.    -   (17) In one embodiment, B is phenyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, Y₃ is        C(O)NR_(10b), and each R₈ is independently halogen or (C₃-C₆)        cycloalkyl.    -   (18) In one embodiment, B is phenyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, Y₃ is        C(O)NR_(10b), and two R₈ together with the atoms to which they        are attached form a (C₅-C₇) cycloalkyl ring.    -   (19) In one embodiment, B is phenyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, Y₃        is C(O)NR_(10b), and each R₈ is independently (C₁-C₄) alkyl,        halogen, or (C₃-C₆) cycloalkyl, or two R₈ together with the        atoms to which they are attached form a (C₅-C₇) cycloalkyl ring.    -   (20) In one embodiment, B is phenyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, Y₃        is C(O)NR_(10b), and each R₈ is independently (C₁-C₄) alkyl,        halogen, or (C₃-C₆) cycloalkyl.    -   (21) In one embodiment, B is phenyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, Y₃        is C(O)NR_(10b), and each R₈ is independently (C₁-C₄) alkyl.    -   (22) In one embodiment, B is phenyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, Y₃        is C(O)NR_(10b), and each R₈ is independently halogen or (C₃-C₆)        cycloalkyl.    -   (23) In one embodiment, B is phenyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, Y₃        is C(O)NR_(10b), and two R₈ together with the atoms to which        they are attached form a (C₅-C₇) cycloalkyl ring.    -   (24) In one embodiment, B is phenyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄)        hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl,        halogen, or (C₃-C₆) cycloalkyl, or two R₈ together with the        atoms to which they are attached form a (C₅-C₇) cycloalkyl ring.    -   (25) In one embodiment, B is phenyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄)        hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl,        halogen, or (C₃-C₆) cycloalkyl.    -   (26) In one embodiment, B is phenyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄)        hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl.    -   (27) In one embodiment, B is phenyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄)        hydroxyalkyl, and each R₈ is independently halogen or (C₃-C₆)        cycloalkyl.    -   (28) In one embodiment, B is phenyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄)        hydroxyalkyl, and two R₈ together with the atoms to which they        are attached form a (C₅-C₇) cycloalkyl ring.    -   (29) In one embodiment, B is phenyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each        R₈ is independently (C₁-C₄) alkyl, halogen, or (C₃-C₆)        cycloalkyl, or two R₈ together with the atoms to which they are        attached form a (C₅-C₇) cycloalkyl ring.    -   (30) In one embodiment, B is phenyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each        R₈ is independently (C₁-C₄) alkyl, halogen, or (C₃-C₆)        cycloalkyl.    -   (31) In one embodiment, B is phenyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each        R₈ is independently (C₁-C₄) alkyl.    -   (32) In one embodiment, B is phenyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each        R₈ is independently halogen or (C₃-C₆) cycloalkyl.    -   (33) In one embodiment, B is phenyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and two        R₈ together with the atoms to which they are attached form a        (C₅-C₇) cycloalkyl ring.    -   (34) In one embodiment, B is phenyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl,        and each R₈ is independently (C₁-C₄) alkyl, halogen, or (C₃-C₆)        cycloalkyl, or two R₈ together with the atoms to which they are        attached form a (C₅-C₇) cycloalkyl ring.    -   (35) In one embodiment, B is phenyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl,        and each R₈ is independently (C₁-C₄) alkyl, halogen, or (C₃-C₆)        cycloalkyl.    -   (36) In one embodiment, B is phenyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl,        and each R₈ is independently (C₁-C₄) alkyl.    -   (37) In one embodiment, B is phenyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl,        and each R₈ is independently halogen or (C₃-C₆) cycloalkyl.    -   (38) In one embodiment, B is phenyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl,        and two R₈ together with the atoms to which they are attached        form a (C₅-C₇) cycloalkyl ring.    -   (39) In one embodiment, B, Y₂, Y₃, R₆, R₇, and R₈ are each as        defined, where applicable, in any one of (1)-(38), and A is        phenyl.    -   (40) In one embodiment, B, Y₂, Y₃, R₆, R₇, and R₈ are each as        defined, where applicable, in any one of (1)-(38), and A is        thiophenyl.    -   (41) In one embodiment, B, Y₂, Y₃, R₆, R₇, and R₈ are each as        defined, where applicable, in any one of (1)-(38), and R_(10a)        is H.    -   (42) In one embodiment, B, Y₂, Y₃, R₆, R₇, and R₈ are each as        defined, where applicable, in any one of (1)-(38), and R_(10b)        is H.    -   (43) In one embodiment, B, Y₂, Y₃, R₆, R₇, and R₈ are each as        defined, where applicable, in any one of (1)-(38), R_(10a) is H,        and R_(10b) is H.    -   (44) In one embodiment, B, Y₂, Y₃, R₆, R₇, and R₈ are each as        defined, where applicable, in any one of (1)-(38), A is phenyl,        and R_(10a) is H.    -   (45) In one embodiment, B, Y₂, Y₃, R₆, R₇, and R₈ are each as        defined, where applicable, in any one of (1)-(38), A is phenyl,        and R_(10b) is H.    -   (46) In one embodiment, B, Y₂, Y₃, R₆, R₇, and R₈ are each as        defined, where applicable, in any one of (1)-(38), A is phenyl,        R_(10a) is H, and R_(10b) is H.    -   (47) In one embodiment, B, Y₂, Y₃, R₆, R₇, and R₈ are each as        defined, where applicable, in any one of (1)-(38), A is        thiophenyl, and R_(10a) is H.    -   (48) In one embodiment, B, Y₂, Y₃, R₆, R₇, and R₈ are each as        defined, where applicable, in any one of (1)-(38), A is        thiophenyl, and R_(10b) is H.    -   (49) In one embodiment, B, Y₂, Y₃, R₆, R₇, and R₈ are each as        defined, where applicable, in any one of (1)-(38), A is        thiophenyl, R_(10a) is H, and R_(10b) is H.    -   (50) In one embodiment, B is phenyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄)        hydroxyalkyl, Y₃ is C(O)NR_(10b), and R₈ and R_(10b) together        with the atoms to which they are attached form a 5- or        6-membered heterocycloalkyl or heteroaryl containing 1 or 2        heteroatoms selected from N, O, and S and optionally substituted        with 1 to 3 R₁₁.    -   (51) In one embodiment, B is phenyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, Y₃ is        C(O)NR_(10b), and R₈ and R_(10b) together with the atoms to        which they are attached form a 5- or 6-membered heterocycloalkyl        or heteroaryl containing 1 or 2 heteroatoms selected from N, O,        and S and optionally substituted with 1 to 3 R₁₁.    -   (52) In one embodiment, B is phenyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, Y₃        is C(O)NR_(10b), and R₈ and R_(10b) together with the atoms to        which they are attached form a 5- or 6-membered heterocycloalkyl        or heteroaryl containing 1 or 2 heteroatoms selected from N, O,        and S and optionally substituted with 1 to 3 R₁₁.    -   (53) In one embodiment, B is phenyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄)        hydroxyalkyl, and R₈ and R_(10b) together with the atoms to        which they are attached form a 5- or 6-membered heterocycloalkyl        or heteroaryl containing 1 or 2 heteroatoms selected from N, O,        and S and optionally substituted with 1 to 3 R₁₁.    -   (54) In one embodiment, B is phenyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and R₈        and R_(10b) together with the atoms to which they are attached        form a 5- or 6-membered heterocycloalkyl or heteroaryl        containing 1 or 2 heteroatoms selected from N, O, and S and        optionally substituted with 1 to 3 R₁₁.    -   (55) In one embodiment, B is phenyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl,        and R₈ and R_(10b) together with the atoms to which they are        attached form a 5- or 6-membered heterocycloalkyl or heteroaryl        containing 1 or 2 heteroatoms selected from N, O, and S and        optionally substituted with 1 to 3 R₁₁.    -   (56) In one embodiment, B, Y₂, Y₃, R₆, R₇, R₈, and R_(10b) are        each as defined, where applicable, in any one of (50)-(55), and        A is phenyl.    -   (57) In one embodiment, B, Y₂, Y₃, R₆, R₇, R₈, and R_(10b) are        each as defined, where applicable, in any one of (50)-(55), and        A is thiophenyl.    -   (58) In one embodiment, B, Y₂, Y₃, R₆, R₇, R₈, and R_(10b) are        each as defined, where applicable, in any one of (50)-(55), and        R_(10a) is H.    -   (59) In one embodiment, B, Y₂, Y₃, R₆, R₇, R₈, and R_(10b) are        each as defined, where applicable, in any one of (50)-(55), A is        phenyl, and R_(10a) is H.    -   (60) In one embodiment, B, Y₂, Y₃, R₆, R₇, R₈, and R_(10b) are        each as defined, where applicable, in any one of (50)-(55), A is        thiophenyl, and R_(10a) is H.    -   (61) In one embodiment, B, Y₂, Y₃, R₆, R₇, R₈, and R_(10b) are        each as defined, where applicable, in any one of (50)-(55), and        R_(10a) is H.    -   (62) In one embodiment, B is pyridinyl and Y₂ is NR_(10a).    -   (63) In one embodiment, B is pyridinyl, Y₂ is NR_(10a), and R₆        is (C₁-C₄) alkyl.    -   (64) In one embodiment, B is pyridinyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, and each R₇ is independently (C₁-C₄) alkyl or        (C₁-C₄) hydroxyalkyl.    -   (65) In one embodiment, B is pyridinyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, and each R₇ is independently (C₁-C₄) alkyl.    -   (66) In one embodiment, B is pyridinyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, and each R₇ is independently (C₁-C₄)        hydroxyalkyl.    -   (67) In one embodiment, B is pyridinyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄)        hydroxyalkyl, and Y₃ is C(O)NR_(10b).    -   (68) In one embodiment, B is pyridinyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and Y₃ is        C(O)NR_(10b).    -   (69) In one embodiment, B is pyridinyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl,        and Y₃ is C(O)NR_(10b).    -   (70) In one embodiment, B is pyridinyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄)        hydroxyalkyl, Y₃ is C(O)NR_(10b), and each R₈ is independently        (C₁-C₄) alkyl, halogen, or (C₃-C₆) cycloalkyl, or two R₈        together with the atoms to which they are attached form a        (C₅-C₇) cycloalkyl ring.    -   (71) In one embodiment, B is pyridinyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄)        hydroxyalkyl, Y₃ is C(O)NR_(10b), and each R₈ is independently        (C₁-C₄) alkyl, halogen, or (C₃-C₆) cycloalkyl.    -   (72) In one embodiment, B is pyridinyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄)        hydroxyalkyl, Y₃ is C(O)NR_(10b), and each R₈ is independently        (C₁-C₄) alkyl.    -   (73) In one embodiment, B is pyridinyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄)        hydroxyalkyl, Y₃ is C(O)NR_(10b), and each R₈ is independently        halogen or (C₃-C₆) cycloalkyl.    -   (74) In one embodiment, B is pyridinyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄)        hydroxyalkyl, Y₃ is C(O)NR_(10b), and two R₈ together with the        atoms to which they are attached form a (C₅-C₇) cycloalkyl ring.    -   (75) In one embodiment, B is pyridinyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, Y₃ is        C(O)NR_(10b), and each R₈ is independently (C₁-C₄) alkyl,        halogen, or (C₃-C₆) cycloalkyl, or two R₈ together with the        atoms to which they are attached form a (C₅-C₇) cycloalkyl ring.    -   (76) In one embodiment, B is pyridinyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, Y₃ is        C(O)NR_(10b), and each R₈ is independently (C₁-C₄) alkyl,        halogen, or (C₃-C₆) cycloalkyl.    -   (77) In one embodiment, B is pyridinyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, Y₃ is        C(O)NR_(10b), and each R₈ is independently (C₁-C₄) alkyl.    -   (78) In one embodiment, B is pyridinyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, Y₃ is        C(O)NR_(10b), and each R₈ is independently halogen or (C₃-C₆)        cycloalkyl.    -   (79) In one embodiment, B is pyridinyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, Y₃ is        C(O)NR_(10b), and two R₈ together with the atoms to which they        are attached form a (C₅-C₇) cycloalkyl ring.    -   (80) In one embodiment, B is pyridinyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, Y₃        is C(O)NR_(10b), and each R₈ is independently (C₁-C₄) alkyl,        halogen, or (C₃-C₆) cycloalkyl, or two R₈ together with the        atoms to which they are attached form a (C₅-C₇) cycloalkyl ring.    -   (81) In one embodiment, B is pyridinyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, Y₃        is C(O)NR_(10b), and each R₈ is independently (C₁-C₄) alkyl,        halogen, or (C₃-C₆) cycloalkyl.    -   (82) In one embodiment, B is pyridinyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, Y₃        is C(O)NR_(10b), and each R₈ is independently (C₁-C₄) alkyl.    -   (83) In one embodiment, B is pyridinyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, Y₃        is C(O)NR_(10b), and each R₈ is independently halogen or (C₃-C₆)        cycloalkyl.    -   (84) In one embodiment, B is pyridinyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, Y₃        is C(O)NR_(10b), and two R₈ together with the atoms to which        they are attached form a (C₅-C₇) cycloalkyl ring.    -   (85) In one embodiment, B is pyridinyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄)        hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl,        halogen, or (C₃-C₆) cycloalkyl, or two R₈ together with the        atoms to which they are attached form a (C₅-C₇) cycloalkyl ring.    -   (86) In one embodiment, B is pyridinyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄)        hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl,        halogen, or (C₃-C₆) cycloalkyl.    -   (87) In one embodiment, B is pyridinyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄)        hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl.    -   (88) In one embodiment, B is pyridinyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄)        hydroxyalkyl, and each R₈ is independently halogen or (C₃-C₆)        cycloalkyl.    -   (89) In one embodiment, B is pyridinyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄)        hydroxyalkyl, and two R₈ together with the atoms to which they        are attached form a (C₅-C₇) cycloalkyl ring.    -   (90) In one embodiment, B is pyridinyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each        R₈ is independently (C₁-C₄) alkyl, halogen, or (C₃-C₆)        cycloalkyl, or two R₈ together with the atoms to which they are        attached form a (C₅-C₇) cycloalkyl ring.    -   (91) In one embodiment, B is pyridinyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each        R₈ is independently (C₁-C₄) alkyl, halogen, or (C₃-C₆)        cycloalkyl.    -   (92) In one embodiment, B is pyridinyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each        R₈ is independently (C₁-C₄) alkyl.    -   (93) In one embodiment, B is pyridinyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each        R₈ is independently halogen or (C₃-C₆) cycloalkyl.    -   (94) In one embodiment, B is pyridinyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and two        R₈ together with the atoms to which they are attached form a        (C₅-C₇) cycloalkyl ring.    -   (95) In one embodiment, B is pyridinyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl,        and each R₈ is independently (C₁-C₄) alkyl, halogen, or (C₃-C₆)        cycloalkyl, or two R₈ together with the atoms to which they are        attached form a (C₅-C₇) cycloalkyl ring.    -   (96) In one embodiment, B is pyridinyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl,        and each R₈ is independently (C₁-C₄) alkyl, halogen, or (C₃-C₆)        cycloalkyl.    -   (97) In one embodiment, B is pyridinyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl,        and each R₈ is independently (C₁-C₄) alkyl.    -   (98) In one embodiment, B is pyridinyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl,        and each R₈ is independently halogen or (C₃-C₆) cycloalkyl.    -   (99) In one embodiment, B is pyridinyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl,        and two R₈ together with the atoms to which they are attached        form a (C₅-C₇) cycloalkyl ring.    -   (100) In one embodiment, B, Y₂, Y₃, R₆, R₇, and R₈ are each as        defined, where applicable, in any one of (62)-(99), and A is        phenyl.    -   (101) In one embodiment, B, Y₂, Y₃, R₆, R₇, and R₈ are each as        defined, where applicable, in any one of (62)-(99), and A is        thiophenyl.    -   (102) In one embodiment, B, Y₂, Y₃, R₆, R₇, and R₈ are each as        defined, where applicable, in any one of (62)-(99), and R_(10a)        is H.    -   (103) In one embodiment, B, Y₂, Y₃, R₆, R₇, and R₈ are each as        defined, where applicable, in any one of (62)-(99), and R_(10b)        is H.    -   (104) In one embodiment, B, Y₂, Y₃, R₆, R₇, and R₈ are each as        defined, where applicable, in any one of (62)-(99), R_(10a) is        H, and R_(10b) is H.    -   (105) In one embodiment, B, Y₂, Y₃, R₆, R₇, and R₈ are each as        defined, where applicable, in any one of v, A is phenyl, and        R_(10a) is H.    -   (106) In one embodiment, B, Y₂, Y₃, R₆, R₇, and R₈ are each as        defined, where applicable, in any one of (62)-(99), A is phenyl,        and R_(10b) is H.    -   (107) In one embodiment, B, Y₂, Y₃, R₆, R₇, and R₈ are each as        defined, where applicable, in any one of (62)-(99), A is phenyl,        R_(10a) is H, and R_(10b) is H.    -   (108) In one embodiment, B, Y₂, Y₃, R₆, R₇, and R₈ are each as        defined, where applicable, in any one of (62)-(99), A is        thiophenyl, and R_(10a) is H.    -   (109) In one embodiment, B, Y₂, Y₃, R₆, R₇, and R₈ are each as        defined, where applicable, in any one of (62)-(99), A is        thiophenyl, and R_(10b) is H.    -   (110) In one embodiment, B, Y₂, Y₃, R₆, R₇, and R₈ are each as        defined, where applicable, in any one of (62)-(99), A is        thiophenyl, R_(10a) is H, and R_(10b) is H.    -   (111) In one embodiment, B is pyridinyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄)        hydroxyalkyl, Y₃ is C(O)NR_(10b), and R₈ and R_(10b) together        with the atoms to which they are attached form a 5- or        6-membered heterocycloalkyl or heteroaryl containing 1 or 2        heteroatoms selected from N, O, and S and optionally substituted        with 1 to 3 R₁₁.    -   (112) In one embodiment, B is pyridinyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, Y₃ is        C(O)NR_(10b), and R₈ and R_(10b) together with the atoms to        which they are attached form a 5- or 6-membered heterocycloalkyl        or heteroaryl containing 1 or 2 heteroatoms selected from N, O,        and S and optionally substituted with 1 to 3 R₁₁.    -   (113) In one embodiment, B is pyridinyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, Y₃        is C(O)NR_(10b), and R₈ and R_(10b) together with the atoms to        which they are attached form a 5- or 6-membered heterocycloalkyl        or heteroaryl containing 1 or 2 heteroatoms selected from N, O,        and S and optionally substituted with 1 to 3 R₁₁.    -   (114) In one embodiment, B is pyridinyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄)        hydroxyalkyl, and R₈ and R_(10b) together with the atoms to        which they are attached form a 5- or 6-membered heterocycloalkyl        or heteroaryl containing 1 or 2 heteroatoms selected from N, O,        and S and optionally substituted with 1 to 3 R₁₁.    -   (115) In one embodiment, B is pyridinyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and R₈        and R_(10b) together with the atoms to which they are attached        form a 5- or 6-membered heterocycloalkyl or heteroaryl        containing 1 or 2 heteroatoms selected from N, O, and S and        optionally substituted with 1 to 3 R₁₁.    -   (116) In one embodiment, B is pyridinyl, Y₂ is NR_(10a), R₆ is        (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl,        and R₈ and R_(10b) together with the atoms to which they are        attached form a 5- or 6-membered heterocycloalkyl or heteroaryl        containing 1 or 2 heteroatoms selected from N, O, and S and        optionally substituted with 1 to 3 R₁₁.    -   (117) In one embodiment, B, Y₂, Y₃, R₆, R₇, R₈, and R_(10b) are        each as defined, where applicable, in any one of (111)-(116),        and A is phenyl.    -   (118) In one embodiment, B, Y₂, Y₃, R₆, R₇, R₈, and R_(10b) are        each as defined, where applicable, in any one of (111)-(116),        and A is thiophenyl.    -   (119) In one embodiment, B, Y₂, Y₃, R₆, R₇, R₈, and R_(10b) are        each as defined, where applicable, in any one of (111)-(116),        and R_(10a) is H.    -   (120) In one embodiment, B, Y₂, Y₃, R₆, R₇, R₈, and R_(10b) are        each as defined, where applicable, in any one of (111)-(116), A        is phenyl, and R_(10a) is H.    -   (121) In one embodiment, B, Y₂, Y₃, R₆, R₇, R₈, and R_(10b) are        each as defined, where applicable, in any one of (111)-(116), A        is thiophenyl, and R_(10a) is H.    -   (122) In one embodiment, B, Y₂, Y₃, R₆, R₇, R₈, and R_(10b) are        each as defined, where applicable, in any one of (111)-(116),        and R_(10a) is H.    -   (123) In one embodiment, B is pyridinyl and A is phenyl.    -   (124) In one embodiment, B is pyridinyl and A is thiophenyl.    -   (125) In one embodiment, B is phenyl and A is phenyl.    -   (126) In one embodiment, B is phenyl and A is thiophenyl.    -   (127) In one embodiment, B is pyridinyl, A is phenyl, and R₆ is        methyl.    -   (128) In one embodiment, B is pyridinyl, A is thiophenyl, and R₆        is methyl.    -   (129) In one embodiment, B is phenyl, A is phenyl, and R₆ is        methyl.    -   (130) In one embodiment, B is phenyl, A is thiophenyl, and R₆ is        methyl.    -   (131) In one embodiment, B is pyridinyl, A is phenyl, and Y₂ is        NR_(10a).    -   (132) In one embodiment, B is pyridinyl, A is thiophenyl, and Y₂        is NR_(10a).    -   (133) In one embodiment, B is phenyl, A is phenyl, and Y₂ is        NR_(10a).    -   (134) In one embodiment, B is phenyl, A is thiophenyl, and Y₂ is        NR_(10a).    -   (135) In one embodiment, B is pyridinyl, A is phenyl, and Y₃ is        C(O)NR_(10b).    -   (136) In one embodiment, B is pyridinyl, A is thiophenyl, and Y₃        is C(O)NR_(10b).    -   (137) In one embodiment, B is phenyl, A is phenyl, and Y₃ is        C(O)NR_(10b).    -   (138) In one embodiment, B is phenyl, A is thiophenyl, and Y₃ is        C(O)NR_(10b).    -   (139) In one embodiment, A, B, Y₂, Y₃, R₆, R₇, R₈, R_(10a), and        R_(10b) are each as defined, where applicable, in any one of        (1)-(138), o1 is 0.    -   (140) In one embodiment, A, B, Y₂, Y₃, R₆, R₇, R₈, R_(10a), and        R_(10b) are each as defined, where applicable, in any one of        (1)-(138), o1 is 1.    -   (141) In one embodiment, A, B, Y₂, Y₃, R₆, R₇, R₈, R_(10a), and        R_(10b) are each as defined, where applicable, in any one of        (1)-(138), o1 is 2.    -   (142) In one embodiment, A, B, Y₂, Y₃, R₆, R₇, R₈, R_(10a), and        R_(10b) are each as defined, where applicable, in any one of        (1)-(138), o1 is 2, and R₅ is (C₁-C₄) alkyl or oxo.    -   (143) In one embodiment, A, B, Y₂, Y₃, R₆, R₇, R₈, R_(10a), and        R_(10b) are each as defined, where applicable, in any one of        (1)-(138), o2 is 1.    -   (144) In one embodiment, A, B, Y₂, Y₃, R₆, R₇, R₈, R_(10a), and        R_(10b) are each as defined, where applicable, in any one of        (1)-(138), o2 is 2.    -   (145) In one embodiment, A, B, Y₂, Y₃, R₆, R₇, R₈, R_(10a), and        R_(10b) are each as defined, where applicable, in any one of        (1)-(138), o1 is 0 and o2 is 1.    -   (146) In one embodiment, A, B, Y₂, Y₃, R₆, R₇, R₈, R_(10a), and        R_(10b) are each as defined, where applicable, in any one of        (1)-(138), o1 is 1 and o2 is 1.    -   (147) In one embodiment, A, B, Y₂, Y₃, R₆, R₇, R₈, R_(10a), and        R_(10b) are each as defined, where applicable, in any one of        (1)-(138), o1 is 2 and o2 is 1.

In one embodiment, the compound of Formula TL-II is of Formula TL-IIa,TL-IIb, or TL-IIc:

wherein A, B, Y₄, R₅, R₆, R₇, R_(10b), and o1 are each as defined abovein Formula TL-II.

For a Targeting Ligand of Formula TL-IIa:

-   -   (1) In one embodiment, B is phenyl.    -   (2) In one embodiment, B is phenyl and R₆ is (C₁-C₄) alkyl.    -   (3) In one embodiment, B is phenyl, R₆ is (C₁-C₄) alkyl, and        each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl.    -   (4) In one embodiment, B is phenyl, R₆ is (C₁-C₄) alkyl, and        each R₇ is independently (C₁-C₄) alkyl.    -   (5) In one embodiment, B is phenyl, R₆ is (C₁-C₄) alkyl, and        each R₇ is independently (C₁-C₄) hydroxyalkyl.    -   (6) In one embodiment, B is phenyl, R₆ is (C₁-C₄) alkyl, each R₇        is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each        R₈ is independently (C₁-C₄) alkyl, halogen, or (C₃-C₆)        cycloalkyl, or two R₈ together with the atoms to which they are        attached form a (C₅-C₇) cycloalkyl ring.    -   (7) In one embodiment, B is phenyl, R₆ is (C₁-C₄) alkyl, each R₇        is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each        R₈ is independently (C₁-C₄) alkyl, halogen, or (C₃-C₆)        cycloalkyl.    -   (8) In one embodiment, B is phenyl, R₆ is (C₁-C₄) alkyl, each R₇        is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each        R₈ is independently (C₁-C₄) alkyl.    -   (9) In one embodiment, B is phenyl, R₆ is (C₁-C₄) alkyl, each R₇        is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each        R₈ is independently halogen or (C₃-C₆) cycloalkyl.    -   (10) In one embodiment, B is phenyl, R₆ is (C₁-C₄) alkyl, each        R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and        two R₈ together with the atoms to which they are attached form a        (C₅-C₇) cycloalkyl ring.    -   (11) In one embodiment, B is phenyl, R₆ is (C₁-C₄) alkyl, each        R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently        (C₁-C₄) alkyl, halogen, or (C₃-C₆) cycloalkyl, or two R₈        together with the atoms to which they are attached form a        (C₅-C₇) cycloalkyl ring.    -   (12) In one embodiment, B is phenyl, R₆ is (C₁-C₄) alkyl, each        R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently        (C₁-C₄) alkyl, halogen, or (C₃-C₆) cycloalkyl.    -   (13) In one embodiment, B is phenyl, R₆ is (C₁-C₄) alkyl, each        R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently        (C₁-C₄) alkyl.    -   (14) In one embodiment, B is phenyl, R₆ is (C₁-C₄) alkyl, each        R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently        halogen or (C₃-C₆) cycloalkyl.    -   (15) In one embodiment, B is phenyl, R₆ is (C₁-C₄) alkyl, each        R₇ is independently (C₁-C₄) alkyl, and two R₈ together with the        atoms to which they are attached form a (C₅-C₇) cycloalkyl ring.    -   (16) In one embodiment, B is phenyl, R₆ is (C₁-C₄) alkyl, each        R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is        independently (C₁-C₄) alkyl, halogen, or (C₃-C₆) cycloalkyl, or        two R₈ together with the atoms to which they are attached form a        (C₅-C₇) cycloalkyl ring.    -   (17) In one embodiment, B is phenyl, R₆ is (C₁-C₄) alkyl, each        R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is        independently (C₁-C₄) alkyl, halogen, or (C₃-C₆) cycloalkyl.    -   (18) In one embodiment, B is phenyl, R₆ is (C₁-C₄) alkyl, each        R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is        independently (C₁-C₄) alkyl.    -   (19) In one embodiment, B is phenyl, R₆ is (C₁-C₄) alkyl, each        R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is        independently halogen or (C₃-C₆) cycloalkyl.    -   (20) In one embodiment, B is phenyl, R₆ is (C₁-C₄) alkyl, each        R₇ is independently (C₁-C₄) hydroxyalkyl, and two R₈ together        with the atoms to which they are attached form a (C₅-C₇)        cycloalkyl ring.    -   (21) In one embodiment, B, R₆, R₇, and R₈ are each as defined,        where applicable, in any one of (1)-(20), and A is phenyl.    -   (22) In one embodiment, B, R₆, R₇, and R₈ are each as defined,        where applicable, in any one of (1)-(20), and A is thiophenyl.    -   (23) In one embodiment, B, R₆, R₇, and R₈ are each as defined,        where applicable, in any one of (1)-(20), and R_(10b) is H.    -   (24) In one embodiment, B, R₆, R₇, and R₈ are each as defined,        where applicable, in any one of (1)-(20), A is phenyl, and        R_(10b) is H.    -   (25) In one embodiment, B, R₆, R₇, and R₈ are each as defined,        where applicable, in any one of (1)-(20), A is thiophenyl, and        R_(10b) is H.    -   (26) In one embodiment, B is phenyl, R₆ is (C₁-C₄) alkyl, each        R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and        R₈ and R_(10b) together with the atoms to which they are        attached form a 5- or 6-membered heterocycloalkyl or heteroaryl        containing 1 or 2 heteroatoms selected from N, O, and S and        optionally substituted with 1 to 3 R₁₁.    -   (27) In one embodiment, B is phenyl, R₆ is (C₁-C₄) alkyl, each        R₇ is independently (C₁-C₄) alkyl, and R₈ and R_(10b) together        with the atoms to which they are attached form a 5- or        6-membered heterocycloalkyl or heteroaryl containing 1 or 2        heteroatoms selected from N, O, and S and optionally substituted        with 1 to 3 R₁₁.    -   (28) In one embodiment, B is phenyl, R₆ is (C₁-C₄) alkyl, each        R₇ is independently (C₁-C₄) hydroxyalkyl, and R₈ and R_(10b)        together with the atoms to which they are attached form a 5- or        6-membered heterocycloalkyl or heteroaryl containing 1 or 2        heteroatoms selected from N, O, and S and optionally substituted        with 1 to 3 R₁₁.    -   (29) In one embodiment, B, R₆, R₇, R₈, and R_(10b) are each as        defined, where applicable, in any one of (26)-(28), and A is        phenyl.    -   (30) In one embodiment, B, R₆, R₇, R₈, and R_(10b) are each as        defined, where applicable, in any one of (26)-(28), and A is        thiophenyl.    -   (31) In one embodiment, B is pyridinyl.    -   (32) In one embodiment, B is pyridinyl and R₆ is (C₁-C₄) alkyl.    -   (33) In one embodiment, B is pyridinyl, R₆ is (C₁-C₄) alkyl, and        each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl.    -   (34) In one embodiment, B is pyridinyl, R₆ is (C₁-C₄) alkyl, and        each R₇ is independently (C₁-C₄) alkyl.    -   (35) In one embodiment, B is pyridinyl, R₆ is (C₁-C₄) alkyl, and        each R₇ is independently (C₁-C₄) hydroxyalkyl.    -   (36) In one embodiment, B is pyridinyl, R₆ is (C₁-C₄) alkyl,        each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl,        and each R₈ is independently (C₁-C₄) alkyl, halogen, or (C₃-C₆)        cycloalkyl, or two R₈ together with the atoms to which they are        attached form a (C₅-C₇) cycloalkyl ring.    -   (37) In one embodiment, B is pyridinyl, R₆ is (C₁-C₄) alkyl,        each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl,        and each R₈ is independently (C₁-C₄) alkyl, halogen, or (C₃-C₆)        cycloalkyl.    -   (38) In one embodiment, B is pyridinyl, R₆ is (C₁-C₄) alkyl,        each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl,        and each R₈ is independently (C₁-C₄) alkyl.    -   (39) In one embodiment, B is pyridinyl, R₆ is (C₁-C₄) alkyl,        each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl,        and each R₈ is independently halogen or (C₃-C₆) cycloalkyl.    -   (40) In one embodiment, B is pyridinyl, R₆ is (C₁-C₄) alkyl,        each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl,        and two R₈ together with the atoms to which they are attached        form a (C₅-C₇) cycloalkyl ring.    -   (41) In one embodiment, B is pyridinyl, R₆ is (C₁-C₄) alkyl,        each R₇ is independently (C₁-C₄) alkyl, and each R₈ is        independently (C₁-C₄) alkyl, halogen, or (C₃-C₆) cycloalkyl, or        two R₈ together with the atoms to which they are attached form a        (C₅-C₇) cycloalkyl ring.    -   (42) In one embodiment, B is pyridinyl, R₆ is (C₁-C₄) alkyl,        each R₇ is independently (C₁-C₄) alkyl, and each R₈ is        independently (C₁-C₄) alkyl, halogen, or (C₃-C₆) cycloalkyl.    -   (43) In one embodiment, B is pyridinyl, R₆ is (C₁-C₄) alkyl,        each R₇ is independently (C₁-C₄) alkyl, and each R₈ is        independently (C₁-C₄) alkyl.    -   (44) In one embodiment, B is pyridinyl, R₆ is (C₁-C₄) alkyl,        each R₇ is independently (C₁-C₄) alkyl, and each R₈ is        independently halogen or (C₃-C₆) cycloalkyl.    -   (45) In one embodiment, B is pyridinyl, R₆ is (C₁-C₄) alkyl,        each R₇ is independently (C₁-C₄) alkyl, and two R₈ together with        the atoms to which they are attached form a (C₅-C₇) cycloalkyl        ring.    -   (46) In one embodiment, B is pyridinyl, R₆ is (C₁-C₄) alkyl,        each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is        independently (C₁-C₄) alkyl, halogen, or (C₃-C₆) cycloalkyl, or        two R₈ together with the atoms to which they are attached form a        (C₅-C₇) cycloalkyl ring.    -   (47) In one embodiment, B is pyridinyl, R₆ is (C₁-C₄) alkyl,        each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is        independently (C₁-C₄) alkyl, halogen, or (C₃-C₆) cycloalkyl.    -   (48) In one embodiment, B is pyridinyl, R₆ is (C₁-C₄) alkyl,        each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is        independently (C₁-C₄) alkyl.    -   (49) In one embodiment, B is pyridinyl, R₆ is (C₁-C₄) alkyl,        each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is        independently halogen or (C₃-C₆) cycloalkyl.    -   (50) In one embodiment, B is pyridinyl, R₆ is (C₁-C₄) alkyl,        each R₇ is independently (C₁-C₄) hydroxyalkyl, and two R₈        together with the atoms to which they are attached form a        (C₅-C₇) cycloalkyl ring.    -   (51) In one embodiment, B, R₆, R₇, and R₈ are each as defined,        where applicable, in any one of (31)-(50), and A is phenyl.    -   (52) In one embodiment, B, R₆, R₇, and R₈ are each as defined,        where applicable, in any one of (31)-(50), and A is thiophenyl.    -   (53) In one embodiment, B, R₆, R₇, and R₈ are each as defined,        where applicable, in any one of (31)-(50), and R_(10b) is H.    -   (54) In one embodiment, B, R₆, R₇, and R₈ are each as defined,        where applicable, in any one of (31)-(50), A is phenyl, and        R_(10b) is H.    -   (55) In one embodiment, B, R₆, R₇, and R₈ are each as defined,        where applicable, in any one of (31)-(50), A is thiophenyl, and        R_(10b) is H.    -   (56) In one embodiment, B is pyridinyl, R₆ is (C₁-C₄) alkyl,        each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl,        and R₈ and R_(10b) together with the atoms to which they are        attached form a 5- or 6-membered heterocycloalkyl or heteroaryl        containing 1 or 2 heteroatoms selected from N, O, and S and        optionally substituted with 1 to 3 R₁₁.    -   (57) In one embodiment, B is pyridinyl, R₆ is (C₁-C₄) alkyl,        each R₇ is independently (C₁-C₄) alkyl, and R₈ and R_(10b)        together with the atoms to which they are attached form a 5- or        6-membered heterocycloalkyl or heteroaryl containing 1 or 2        heteroatoms selected from N, O, and S and optionally substituted        with 1 to 3 R₁₁.    -   (58) In one embodiment, B is pyridinyl, R₆ is (C₁-C₄) alkyl,        each R₇ is independently (C₁-C₄) hydroxyalkyl, and R₈ and        R_(10b) together with the atoms to which they are attached form        a 5- or 6-membered heterocycloalkyl or heteroaryl containing 1        or 2 heteroatoms selected from N, O, and S and optionally        substituted with 1 to 3 R₁₁.    -   (59) In one embodiment, B, R₆, R₇, R₈, and R_(10b) are each as        defined, where applicable, in any one of (56)-(58), and A is        phenyl.    -   (60) In one embodiment, B, R₆, R₇, R₈, and R_(10b) are each as        defined, where applicable, in any one of (56)-(58), and A is        thiophenyl.    -   (61) In one embodiment, B is pyridinyl and A is phenyl.    -   (62) In one embodiment, B is pyridinyl and A is thiophenyl.    -   (63) In one embodiment, B is phenyl and A is phenyl.    -   (64) In one embodiment, B is phenyl and A is thiophenyl.    -   (65) In one embodiment, B is pyridinyl, A is phenyl, and R₆ is        methyl.    -   (66) In one embodiment, B is pyridinyl, A is thiophenyl, and R₆        is methyl.    -   (67) In one embodiment, B is phenyl, A is phenyl, and R₆ is        methyl.    -   (68) In one embodiment, B is phenyl, A is thiophenyl, and R₆ is        methyl.    -   (69) In one embodiment, B is pyridinyl, and A is phenyl.    -   (70) In one embodiment, B is pyridinyl, and A is thiophenyl.    -   (71) In one embodiment, B is phenyl, and A is phenyl.    -   (72) In one embodiment, B is phenyl, and A is thiophenyl.    -   (73) In one embodiment, A, B, R₆, R₇, R₈, and R_(10b) are each        as defined, where applicable, in any one of (1)-(72), o1 is 0.    -   (74) In one embodiment, A, B, R₆, R₇, R₈, and R_(10b) are each        as defined, where applicable, in any one of (1)-(72), o1 is 1.    -   (75) In one embodiment, A, B, R₆, R₇, R₈, and R_(10b) are each        as defined, where applicable, in any one of (1)-(72), o1 is 2.    -   (76) In one embodiment, A, B, R₆, R₇, R₈, and R_(10b) are each        as defined, where applicable, in any one of (1)-(72), o1 is 2,        and R₅ is (C₁-C₄) alkyl or oxo.

A, B, R₅, R₆, R₇, R₈, R_(10b), and o1 can each be selected from any ofthe groups and combined as described above in Formula TL-II.

In one embodiment, a Targeting Ligand is a compound of Formula TL-III:

or an enantiomer, diastereomer, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein:

Z is NR₁₇,

each R₁₂ is independently H, (C₁-C₄) alkyl, or (C₁-C₄) haloalkyl;

R₁₃ is H, (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, or CN;

each R₁₄ is independently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄)alkoxy, (C₁-C₄) haloalkoxy, halogen, O-phenyl, OH, or NH₂;

R₁₅ is H, (C₁-C₄) alkyl, halogen, or CN;

each R₁₆ is independently H, (C₁-C₄) alkyl, or (C₁-C₄) haloalkyl;

R₁₇ is H, (C₁-C₄) alkyl, or (C₁-C₄) haloalkyl;

each R₁₈ is independently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄)alkoxy, (C₁-C₄) haloalkoxy, halogen, or oxo;

s1 and s5 are each independently 0, 1, 2 or 3; and

s2, s3, and s4 are each independently 0 or 1,

wherein the Targeting Ligand is bonded to the Linker via the

next to Z.

In some embodiments, Z is NR₁₇. In other embodiments, Z is

In other embodiments, Z is

In other embodiments, Z is NR₁₇ or

In other embodiments, Z is NR₁₇ or

In other embodiments, Z is

In some embodiments, R₁₇ is H, (C₁-C₃) alkyl, or (C₁-C₃) haloalkyl. Inother embodiments, R₁₇ is (C₁-C₃) alkyl or (C₁-C₃) haloalkyl. In otherembodiments, R₁₇ is H or (C₁-C₃) alkyl. In other embodiments, R₁₇ is H,methyl, ethyl, n-propyl, or i-propyl. In other embodiments, R₁₇ is H,methyl, or ethyl. In other embodiments, R₁₇ is methyl.

In some embodiments, each R₁₈ is independently (C₁-C₃) alkyl, (C₁-C₃)haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, halogen, or oxo. In otherembodiments, each R₁₈ is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl,(C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, or halogen. In other embodiments,each R₁₈ is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, halogen, oroxo. In other embodiments, each R₁₈ is independently (C₁-C₃) alkoxy,(C₁-C₃) haloalkoxy, halogen, or oxo. In other embodiments, each R₁₈ isindependently halogen or oxo. In other embodiments, each R₁₈ isindependently (C₁-C₃) alkyl, halogen, or oxo. In other embodiments, eachR₁₈ is independently methyl, ethyl, n-propyl, i-propyl, F, Cl, Br, I, oroxo. In other embodiments, each R₁₈ is independently methyl, ethyl,n-propyl, i-propyl, F, Cl, or oxo.

In some embodiments, each R₁₂ is independently H, (C₁-C₃) alkyl, or(C₁-C₃) haloalkyl. In other embodiments, each R₁₂ is independently(C₁-C₃) alkyl or (C₁-C₃) haloalkyl. In other embodiments, each R₁₂ isindependently H or (C₁-C₃) alkyl. In other embodiments, each R₁₂ isindependently H, methyl, ethyl, n-propyl, or i-propyl. In otherembodiments, each R₁₂ is independently H, methyl, or ethyl. In otherembodiments, each R₁₂ is independently H or methyl. In otherembodiments, each R₁₂ is H.

In some embodiments, R₁₃ is H, (C₁-C₃) alkyl, (C₁-C₃) haloalkyl or CN.In other embodiments, R₁₃ is (C₁-C₃) alkyl, (C₁-C₃) haloalkyl or CN. Inother embodiments, R₁₃ is H, (C₁-C₃) alkyl, or (C₁-C₃) haloalkyl. Inother embodiments, R₁₃ is (C₁-C₃) alkyl or (C₁-C₃) haloalkyl. In otherembodiments, R₁₃ is H or CN. In other embodiments, R₁₃ is H.

In some embodiments, each R₁₄ is independently (C₁-C₃) alkyl, (C₁-C₃)haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, halogen, O-phenyl, OH, orNH₂. In other embodiments, each R₁₄ is independently (C₁-C₃) alkyl,(C₁-C₃) haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, or halogen. Inother embodiments, each R₁₄ is independently (C₁-C₃) alkyl, (C₁-C₃)haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, or O-phenyl. In otherembodiments, each R₁₄ is independently (C₁-C₃) alkoxy, (C₁-C₃)haloalkoxy, O-phenyl, or OH. In other embodiments, each R₁₄ isindependently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, (C₁-C₃) alkoxy, or(C₁-C₃) haloalkoxy. In other embodiments, each R₁₄ is independentlyO-phenyl, OH, or NH₂. In other embodiments, each R₁₄ is independently(C₁-C₃) alkyl, (C₁-C₃) haloalkyl, (C₁-C₃) alkoxy, halogen, or O-phenyl.In other embodiments, each R₁₄ is independently (C₁-C₄) alkyl, halogen,or O-phenyl. In other embodiments, each R₁₄ is independently methyl,ethyl, n-propyl, i-propyl, F, Cl, Br, I, or O-phenyl. In otherembodiments, each R₁₄ is independently methyl, F, Cl, or O-phenyl. Inother embodiments, each R₁₄ is independently F, Cl, Br, I, or O-phenyl.In other embodiments, each R₁₄ is independently F, Cl, or O-phenyl. Inother embodiments, each R₁₄ is independently F or O-phenyl.

In some embodiments, R₁₅ is H, (C₁-C₃) alkyl, halogen, or CN. In otherembodiments, R₁₅ is (C₁-C₃) alkyl, halogen, or CN. In other embodiments,R₁₅ is H, (C₁-C₃) alkyl, or CN. In other embodiments, R₁₅ is H, methyl,ethyl, n-propyl, i-propyl, or CN. In other embodiments, R₁₅ is H,methyl, ethyl, or CN. In other embodiments, R₁₅ is H, methyl, or CN. Inother embodiments, R₁₅ is H or CN.

In some embodiments, each R₁₆ is independently H, (C₁-C₃) alkyl, or(C₁-C₃) haloalkyl. In other embodiments, each R₁₆ is independently(C₁-C₃) alkyl or (C₁-C₃) haloalkyl. In other embodiments, each R₁₆ isindependently H or (C₁-C₃) alkyl. In other embodiments, each R₁₆ isindependently H, methyl, ethyl, n-propyl, or i-propyl. In otherembodiments, each R₁₆ is independently H, methyl, or ethyl. In otherembodiments, each R₁₆ is independently H or methyl. In otherembodiments, each R₁₆ is H. In other embodiments, each R₁₆ is methyl. Inother embodiments, one R₁₆ is H and the other R₁₆ is methyl.

In some embodiments, s1 is 0. In other embodiments, s1 is 1. In otherembodiments, s1 is 2. In other embodiments, s1 is 3. In otherembodiments, s1 is 0 or 1. In other embodiments, s1 is 1 or 2. In otherembodiments, s1 is 2 or 3. In other embodiments, s1 is 0, 1, or 2. Inother embodiments, s1 is 1, 2, or 3.

In some embodiments, s2 is 0. In other embodiments, s2 is 1.

In some embodiments, s3 is 0. In other embodiments, s3 is 1.

In some embodiments, s4 is 0. In other embodiments, s4 is 1.

In some embodiments, s5 is 0. In other embodiments, s5 is 1. In otherembodiments, s5 is 2. In other embodiments, s5 is 3. In otherembodiments, s5 is 0 or 1. In other embodiments, s5 is 1 or 2. In otherembodiments, s5 is 2 or 3. In other embodiments, s5 is 0, 1, or 2. Inother embodiments, s5 is 1, 2, or 3.

Any of the groups described herein for any of Z, R₁₂, R₁₃, R₁₄, R₁₅,R₁₆, R₁₇, R₁₈, s1, s2, s3, s4, and s5 can be combined with any of thegroups described herein for one or more of the remainder of Z, R₁₂, R₁₃,R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, s1, s2, s3, s4, and s5, and may further becombined with any of the groups described herein for the Linker.

For a Targeting Ligand of Formula TL-III:

-   -   (1) In one embodiment, each R₁₂ is H and R₁₃ is H.    -   (2) In one embodiment, each R₁₂ is H, R₁₃ is H, and s2 is 0.    -   (3) In one embodiment, each R₁₂ is H, R₁₃ is H, and s2 is 1.    -   (4) In one embodiment, each R₁₂ is H, R₁₃ is H, s2 is 0, and s3        is 0.    -   (5) In one embodiment, each R₁₂ is H, R₁₃ is H, s2 is 1, and s3        is 0.    -   (6) In one embodiment, each R₁₂ is H, R₁₃ is H, s2 is 0, and s3        is 1.    -   (7) In one embodiment, each R₁₂ is H, R₁₃ is H, s2 is 1, and s3        is 1.    -   (8) In one embodiment, each R₁₂ is H, R₁₃ is H, s2 is 0, s3 is        0, and each R₁₄ is independently halogen or O-phenyl.    -   (9) In one embodiment, each R₁₂ is H, R₁₃ is H, s2 is 1, s3 is        0, and each R₁₄ is independently halogen or O-phenyl.    -   (10) In one embodiment, each R₁₂ is H, R₁₃ is H, s2 is 0, s3 is        1, and each R₁₄ is independently halogen or O-phenyl.    -   (11) In one embodiment, each R₁₂ is H, R₁₃ is H, s2 is 1, s3 is        1, and each R₁₄ is independently halogen or O-phenyl.    -   (12) In one embodiment, each R₁₂ is H, R₁₃ is H, s2 is 0, s3 is        0, each R₁₄ is independently halogen or O-phenyl, and R₁₅ is H        or CN.    -   (13) In one embodiment, each R₁₂ is H, R₁₃ is H, s2 is 1, s3 is        0, each R₁₄ is independently halogen or O-phenyl, and R₁₅ is H        or CN.    -   (14) In one embodiment, each R₁₂ is H, R₁₃ is H, s2 is 0, s3 is        1, each R₁₄ is independently halogen or O-phenyl, and R₁₅ is H        or CN.    -   (15) In one embodiment, each R₁₂ is H, R₁₃ is H, s2 is 1, s3 is        1, each R₁₄ is independently halogen or O-phenyl, and R₁₅ is H        or CN.    -   (16) In one embodiment, each R₁₂ is H, R₁₃ is H, s2 is 0, s3 is        0, each R₁₄ is independently halogen or O-phenyl, R₁₅ is H or        CN, and each R₁₆ is independently H or (C₁-C₄) alkyl.    -   (17) In one embodiment, each R₁₂ is H, R₁₃ is H, s2 is 1, s3 is        0, each R₁₄ is independently halogen or O-phenyl, R₁₅ is H or        CN, and each R₁₆ is independently H or (C₁-C₄) alkyl.    -   (18) In one embodiment, each R₁₂ is H, R₁₃ is H, s2 is 0, s3 is        1, each R₁₄ is independently halogen or O-phenyl, R₁₅ is H or        CN, and each R₁₆ is independently H or (C₁-C₄) alkyl.    -   (19) In one embodiment, each R₁₂ is H, R₁₃ is H, s2 is 1, s3 is        1, each R₁₄ is independently halogen or O-phenyl, R₁₅ is H or        CN, and each R₁₆ is independently H or (C₁-C₄) alkyl.    -   (20) In one embodiment, Z is NR₁₇ and R₁₇ is H or (C₁-C₃) alkyl.    -   (21) In one embodiment, Z is NR₁₇ and R₁₇ is H, methyl or ethyl.    -   (22) In one embodiment, Z is NR₁₇ and R₁₇ is H.    -   (23) In one embodiment, Z is NR₁₇ and R₁₇ is methyl or ethyl.    -   (24) In one embodiment, Z is

and R₁₇ is H or (C₁-C₃) alkyl.

-   -   (25) In one embodiment, Z is

and R₁₇ is H, methyl or ethyl.

-   -   (26) In one embodiment, Z is

and R₁₇ is H.

-   -   (27) In one embodiment, Z is

and R₁₇ is methyl or ethyl.

-   -   (28) In one embodiment, Z is

and s5 is 0.

-   -   (29) In one embodiment, Z is NR₁₇, R₁₇ is H or (C₁-C₃) alkyl,        and R₁₅ is H or CN.    -   (30) In one embodiment, Z is NR₁₇, R₁₇ is H, methyl or ethyl,        and R₁₅ is H or CN.    -   (31) In one embodiment, Z is NR₁₇, R₁₇ is H, and R₁₅ is H or CN.    -   (32) In one embodiment, Z is NR₁₇, R₁₇ is methyl or ethyl, and        R₁₅ is H or CN.    -   (33) In one embodiment, Z is

R₁₇ is H or (C₁-C₃) alkyl, and R₁₅ is H or CN.

-   -   (34) In one embodiment, Z is

R₁₇ is H, methyl or ethyl, and R₁₅ is H or CN.

-   -   (35) In one embodiment, Z is

R₁₇ is H, and R₁₅ is H or CN.

-   -   (36) In one embodiment, Z is

R₁₇ is methyl or ethyl, and R₁₈ is H or CN.

-   -   (37) In one embodiment, Z is

s5 is 0, and R₁₅ is H or CN.

-   -   (38) In one embodiment, each R₁₆ is methyl. In other        embodiments, each R₁₆ is H. In yet other embodiments one R₁₆ is        H and the other R₁₆ is methyl.    -   (39) In one embodiment, Z is NR₁₇ and s2 is 0.    -   (40) In one embodiment, Z is NR₁₇ and s2 is 1.    -   (41) In one embodiment, Z is NR₁₇ and s3 is 0.    -   (42) In one embodiment, Z is NR₁₇ and s3 is 1.    -   (43) In one embodiment, Z is NR₁₇, s2 is 0, and s3 is 0.    -   (44) In one embodiment, Z is NR₁₇, s2 is 1, and s3 is 0.    -   (45) In one embodiment, Z is NR₁₇, s2 is 0, and s3 is 1.    -   (46) In one embodiment, Z is NR₁₇, s2 is 1, and s3 is 1.    -   (47) In one embodiment, Z is

and s2 is 0.

-   -   (48) In one embodiment, Z is

and s2 is 1.

-   -   (49) In one embodiment, Z is

and s3 is 0.

-   -   (50) In one embodiment, Z is

and s3 is 1.

-   -   (51) In one embodiment, Z is

s2 is 0, and s3 is 0.

-   -   (52) In one embodiment, Z is

s2 is 1, and s3 is 0.

-   -   (53) In one embodiment, Z is

s2 is 0, and s3 is 1.

-   -   (54) In one embodiment, Z is

s2 is 1, and s3 is 1.

-   -   (55) In one embodiment, Z is

and s2 is 0.

-   -   (56) In one embodiment, Z is

and s2 is 1.

-   -   (57) In one embodiment, Z is

and s3 is 0.

-   -   (58) In one embodiment, Z is

and s3 is 1.

-   -   (59) In one embodiment, Z is

s2 is 0, and s3 is 0.

-   -   (60) In one embodiment, Z is

s2 is 1, and s3 is 0.

-   -   (61) In one embodiment, Z is

s2 is 0, and s3 is 1.

-   -   (62) In one embodiment, Z is

s2 is 1, and s3 is 1.

-   -   (63) In one embodiment, Z, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, s2, s3        and s5 are each as defined, where applicable, in any one of        (1)-(62), s1 is 1.    -   (64) In one embodiment, Z, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, s2, s3        and s5 are each as defined, where applicable, in any one of        (1)-(62), s1 is 2.    -   (65) In one embodiment, Z, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, s2, s3        and s5 are each as defined, where applicable, in any one of        (1)-(62), s4 is 0.    -   (66) In one embodiment, Z, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, s2, s3        and s5 are each as defined, where applicable, in any one of        (1)-(62), s4 is 1.

Z, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, s1, s2, s3, s4, and s5 can each beselected from any of the groups and combined as described above inFormula TL-III.

In one embodiment, the compound of Formula TL-III is of Formula TL-IIIa:

wherein Z, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, s2, s3, s4, and s5 are each asdefined above in Formula TL-III.

For a Targeting Ligand of Formula TL-IIIa:

-   -   (1) In one embodiment, s2 is 0, and s3 is 0.    -   (2) In one embodiment, s2 is 1, and s3 is 0.    -   (3) In one embodiment, s2 is 0, and s3 is 1.    -   (4) In one embodiment, s2 is 1, and s3 is 1.    -   (5) In one embodiment, s2 is 0, s3 is 0, and each R₁₄ is        independently halogen or O-phenyl.    -   (6) In one embodiment, s2 is 1, s3 is 0, and each R₁₄ is        independently halogen or O-phenyl.    -   (7) In one embodiment, s2 is 0, s3 is 1, and each R₁₄ is        independently halogen or O-phenyl.    -   (8) In one embodiment, s2 is 1, s3 is 1, and each R₁₄ is        independently halogen or O-phenyl.    -   (9) In one embodiment, s2 is 0, s3 is 0, each R₁₄ is        independently halogen or O-phenyl, and R₁₅ is H or CN.    -   (10) In one embodiment, s2 is 1, s3 is 0, each R₁₄ is        independently halogen or O-phenyl, and R₁₅ is H or CN.    -   (11) In one embodiment, s2 is 0, s3 is 1, each R₁₄ is        independently halogen or O-phenyl, and R₁₅ is H or CN.    -   (12) In one embodiment, s2 is 1, s3 is 1, each R₁₄ is        independently halogen or O-phenyl, and R₁₅ is H or CN.    -   (13) In one embodiment, s2 is 0, s3 is 0, each R₁₄ is        independently halogen or O-phenyl, R₁₅ is H or CN, and each R₁₆        is independently H or (C₁-C₄) alkyl.    -   (14) In one embodiment, s2 is 1, s3 is 0, each R₁₄ is        independently halogen or O-phenyl, R₁₅ is H or CN, and each R₁₆        is independently H or (C₁-C₄) alkyl.    -   (15) In one embodiment, s2 is 0, s3 is 1, each R₁₄ is        independently halogen or O-phenyl, R₁₅ is H or CN, and each R₁₆        is independently H or (C₁-C₄) alkyl.    -   (16) In one embodiment, s2 is 1, s3 is 1, each R₁₄ is        independently halogen or O-phenyl, R₁₅ is H or CN, and each R₁₆        is independently H or (C₁-C₄) alkyl.    -   (17) In one embodiment, Z is NR₁₇ and R₁₇ is H or (C₁-C₃) alkyl.    -   (18) In one embodiment, Z is NR₁₇ and R₁₇ is H, methyl or ethyl.    -   (19) In one embodiment, Z is NR₁₇ and R₁₇ is H.    -   (20) In one embodiment, Z is NR₁₇ and R₁₇ is methyl or ethyl.    -   (21) In one embodiment, Z is

and R₁₇ is H or (C₁-C₃) alkyl.

-   -   (22) In one embodiment, Z is

and R₁₇ is H, methyl or ethyl.

-   -   (23) In one embodiment, Z is

and R₁₇ is H.

-   -   (24) In one embodiment, Z is

and R₁₇ is methyl or ethyl.

-   -   (25) In one embodiment, Z is

and s5 is 0.

-   -   (26) In one embodiment, Z is NR₁₇, R₁₇ is H or (C₁-C₃) alkyl,        and R₁₅ is H or CN.    -   (27) In one embodiment, Z is NR₁₇, R₁₇ is H, methyl or ethyl,        and R₁₅ is H or CN.    -   (28) In one embodiment, Z is NR₁₇, R₁₇ is H, and R₁₅ is H or CN.    -   (29) In one embodiment, Z is NR₁₇, R₁₇ is methyl or ethyl, and        R₁₅ is H or CN.    -   (30) In one embodiment, Z is

R₁₇ is H or (C₁-C₃) alkyl, and R₁₅ is H or CN.

-   -   (31) In one embodiment, Z is

R₁₇ is H, methyl or ethyl, and R₁₅ is H or CN.

-   -   (32) In one embodiment, Z is

R₁₁ is H, and R₁₅ is H or CN.

-   -   (33) In one embodiment, Z is

R₁₇ is methyl or ethyl, and R₁₅ is H or CN.

-   -   (34) In one embodiment, Z is

s5 is 0, and R₁₅ is H or CN.

-   -   (35) In one embodiment, each R₁₆ is methyl. In other        embodiments, each R₁₆ is H. In yet other embodiments one R₁₆ is        H and the other R₁₆ is methyl.    -   (36) In one embodiment, Z is NR₁₇ and s2 is 0.    -   (37) In one embodiment, Z is NR₁₇ and s2 is 1.    -   (38) In one embodiment, Z is NR₁₇ and s3 is 0.    -   (39) In one embodiment, Z is NR₁₇ and s3 is 1.    -   (40) In one embodiment, Z is NR₁₇, s2 is 0, and s3 is 0.    -   (41) In one embodiment, Z is NR₁₇, s2 is 1, and s3 is 0.    -   (42) In one embodiment, Z is NR₁₇, s2 is 0, and s3 is 1.    -   (43) In one embodiment, Z is NR₁₇, s2 is 1, and s3 is 1.    -   (44) In one embodiment, Z is

and s2 is 0.

-   -   (45) In one embodiment, Z is

and s2 is 1.

-   -   (46) In one embodiment, Z is

and s3 is 0

-   -   (47) In one embodiment, Z is

s2 is 0, and s3 is 1.

-   -   (48) In one embodiment, Z is

s2 is 0, and s3 is 0.

-   -   (49) In one embodiment, Z is

s2 is 1, and s3 is 1.

-   -   (50) In one embodiment, Z is

s2 is 0, and s3 is 1.

-   -   (51) In one embodiment, Z is

s2 is 1, and s3 is 1.

-   -   (52) In one embodiment, Z is

and s2 is 0.

-   -   (53) In one embodiment, Z is

and s2 is 1.

-   -   (54) In one embodiment, Z is

and s3 is 0.

-   -   (55) In one embodiment, Z is

and s3 is 1.

-   -   (56) In one embodiment, Z is

s2 is 0, and s3 is 0.

-   -   (57) In one embodiment, Z is

s2 is 1, and s3 is 0.

-   -   (58) In one embodiment, Z is

s2 is 0, and s3 is 1.

-   -   (59) In one embodiment, Z is

s2 is 1, and s3 is 1.

-   -   (60) In one embodiment, Z, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, s2, s3, and        s5 are each as defined, where applicable, in any one of        (1)-(59), s4 is 0.    -   (61) In one embodiment, Z, R₁₄, R₁₅, R₁₆, R₁₇, s2, s3 and s5 are        each as defined, where applicable, in any one of (1)-(59), s4 is        1.

Z, R₁₄, R₁₅, R₁₆, R₁₇, s2, s3, s4, and s5 can each be selected from anyof the groups and combined as described above in Formula TL-III orTL-IIIa.

In one embodiment, the compound of Formula TL-III is of Formula TL-IIIb:

wherein Z, R₁₅, R₁₆, R₁₇, R₁₈, s2, s3, s4, and s5 are each as definedabove in Formula TL-III.

For a Targeting Ligand of Formula TL-IIIb:

-   -   (1) In one embodiment, s2 is 0, and s3 is 0.    -   (2) In one embodiment, s2 is 1, and s3 is 0.    -   (3) In one embodiment, s2 is 0, and s3 is 1.    -   (4) In one embodiment, s2 is 1, and s3 is 1.    -   (5) In one embodiment, s2 is 0, s3 is 0, and R₁₅ is H or CN.    -   (6) In one embodiment, s2 is 1, s3 is 0, and R₁₅ is H or CN.    -   (7) In one embodiment, s2 is 0, s3 is 1, and R₁₅ is H or CN.    -   (8) In one embodiment, s2 is 1, s3 is 1, and R₁₅ is H or CN.    -   (9) In one embodiment, s2 is 0, s3 is 0, R₁₅ is H or CN, and        each R₁₆ is independently H or (C₁-C₄) alkyl.    -   (10) In one embodiment, s2 is 1, s3 is 0, R₁₅ is H or CN, and        each R₁₆ is independently H or (C₁-C₄) alkyl.    -   (11) In one embodiment, s2 is 0, s3 is 1, R₁₅ is H or CN, and        each R₁₆ is independently H or (C₁-C₄) alkyl.    -   (12) In one embodiment, s2 is 1, s3 is 1, R₁₅ is H or CN, and        each R₁₆ is independently H or (C₁-C₄) alkyl.    -   (13) In one embodiment, Z is NR₁₇ and R₁₇ is H or (C₁-C₃) alkyl.    -   (14) In one embodiment, Z is NR₁₇ and R₁₇ is H, methyl or ethyl.    -   (15) In one embodiment, Z is NR₁₇ and R₁₇ is H.    -   (16) In one embodiment, Z is NR₁₇ and R₁₇ is methyl or ethyl.    -   (17) In one embodiment, Z is

and R₁₇ is H or (C₁-C₃) alkyl.

-   -   (18) In one embodiment, Z is

and R₁₇ is H, methyl or ethyl.

-   -   (19) In one embodiment, Z is

-   -   (20) In one embodiment, Z is

and R₁₇ is methyl or ethyl.

-   -   (21) In one embodiment, Z is

and s5 is 0.

-   -   (22) In one embodiment, Z is NR₁₇, R₁₇ is H or (C₁-C₃) alkyl,        and R₁₅ is H or CN.    -   (23) In one embodiment, Z is NR₁₇, R₁₇ is H, methyl or ethyl,        and R₁₅ is H or CN.    -   (24) In one embodiment, Z is NR₁₇, R₁₇ is H, and R₁₅ is H or CN.    -   (25) In one embodiment, Z is NR₁₇, R₁₇ is methyl or ethyl, and        R₁₅ is H or CN.    -   (26) In one embodiment, Z is

R₁₇ is H or (C₁-C₃) alkyl, and R₁₅ is H or CN.

-   -   (27) In one embodiment, Z is

R₁₇ is H, methyl or ethyl, and R₁ is H or CN.

-   -   (28) In one embodiment, Z is

R₁ is H, and R₁₅ is H or CN.

-   -   (29) In one embodiment, Z is

R₁₇ is methyl or ethyl, and R₁₅ is H or CN.

-   -   (30) In one embodiment, Z is

s5 is 0, and R₁₅ is H or CN.

-   -   (31) In one embodiment, each R₁₆ is methyl. In other        embodiments, each R₁₆ is H. In yet other embodiments one R₁₆ is        H and the other R₁₆ is methyl.    -   (32) In one embodiment, Z is NR₁₇ and s2 is 0.    -   (33) In one embodiment, Z is NR₁₇ and s2 is 1.    -   (34) In one embodiment, Z is NR₁₇ and s3 is 0.    -   (35) In one embodiment, Z is NR₁₇ and s3 is 1.    -   (36) In one embodiment, Z is NR₁₇, s2 is 0, and s3 is 0.    -   (37) In one embodiment, Z is NR₁₇, s2 is 1, and s3 is 0.    -   (38) In one embodiment, Z is NR₁₇, s2 is 0, and s3 is 1.    -   (39) In one embodiment, Z is NR₁₇, s2 is 1, and s3 is 1.    -   (40) In one embodiment, Z is

and s2 is 0.

-   -   (41) In one embodiment, Z is

and s2 is 1.

-   -   (42) In one embodiment, Z is

and s3 is 0.

-   -   (43) In one embodiment, Z is

and s3 is 1.

-   -   (44) In one embodiment, Z is

s2 is 0, and s3 is 0.

-   -   (45) In one embodiment, Z is

s2 is 1, and s3 is 0.

-   -   (46) In one embodiment, Z is

s2 is 0, and s3 is 1.

-   -   (47) In one embodiment, Z is

s2 is 1, and s3 is 1.

-   -   (48) In one embodiment, Z is

and s2 is 0.

-   -   (49) In one embodiment, Z is

and s2 is 1.

-   -   (50) In one embodiment, Z is

and s3 is 0.

-   -   (51) In one embodiment, Z is

and s3 is 1.

-   -   (52) In one embodiment, Z is

s2 is 0, and s3 is 0.

-   -   (53) In one embodiment, Z is

s2 is 1, and s3 is 0.

-   -   (54) In one embodiment, Z is

s2 is 0, and s3 is 1.

-   -   (55) In one embodiment, Z is

s2 is 1, and s3 is 1.

-   -   (56) In one embodiment, Z, R₁₅, R₁₆, R₁₇, R₁₈, s2, s3, and s5        are each as defined, where applicable, in any one of (1)-(55),        s4 is 0.    -   (57) In one embodiment, Z, R₁₅, R₁₆, R₁₇, R₁₈, s2, s3, and s5        are each as defined, where applicable, in any one of (1)-(55),        s4 is 1.

Z, R₁₅, R₁₆, R₁₇, R₁₈, s2, s3, s4, and s5 can each be selected from anyof the groups and combined as described above in Formula TL-III orTL-IIIb.

Degron

The Degron serves to link a targeted protein, through a Linker and aTargeting Ligand, to a ubiquitin ligase for proteosomal degradation. Inone embodiment, the Degron is capable of binding to a ubiquitin ligase,such as an E3 ubiquitin ligase. In one embodiment, the Degron is capableof binding to cereblon.

In one embodiment, the Degron is of Formula D1:

or an enantiomer, diastereomer, or stereoisomer thereof, wherein:

Y is a bond, (CH₂)₁₋₆, (CH₂)₀₋₆—O, (CH₂)₀₋₆—C(O)NR₂₆, (CH₂)₀₋₆—NR₂₆C(O),(CH₂)₀₋₆—NH, or (CH₂)₀₋₆—NR₂₇;

Z₃ is C(O) or C(R₂₈)₂;

R₂₆ is H or C₁-C₆ alkyl;

R₂₇ is C₁-C₆ alkyl or C(O)—C₁-C₆ alkyl;

each R₂₈ is independently H or C₁-C₃ alkyl;

each R₂₉ is independently C₁-C₃ alkyl;

R₃₀ is H, deuterium, C₁-C₃ alkyl, F, or Cl;

each R₃₁ is independently halogen, OH, C₁-C₆ alkyl, or C₁-C₆ alkoxy;

q is 0, 1, or 2; and

v is 0, 1, 2, or 3,

wherein the Degron is covalently bonded to the Linker via

In one embodiment, Z₃ is C(O).

In one embodiment, Z₃ is C(O) or CH₂.

In one embodiment, Z₃ is C(R₂₈)₂; and each R₂₈ is H. In one embodiment,Z₃ is C(R₂₈)₂; and one of R₂₈ is H, and the other is C₁-C₃ alkylselected from methyl, ethyl, and propyl. In one embodiment, Z₃ isC(R₂₈)₂; and each R₂₈ is independently selected from methyl, ethyl, andpropyl.

In one embodiment, Y is a bond.

In one embodiment, Y is a bond, O, or NH.

In one embodiment, Y is (CH₂)₁, (CH₂)₂, (CH₂)₃, (CH₂)₄, (CH₂)₅, or(CH₂)₆. In one embodiment, Y is (CH₂)₁, (CH₂)₂, or (CH₂)₃. In oneembodiment, Y is (CH₂)₁ or (CH₂)₂.

In one embodiment, Y is O, CH₂—O, (CH₂)₂—O, (CH₂)₃—O, (CH₂)₄—O,(CH₂)₅—O, or (CH₂)₆—O, In one embodiment, Y is O, CH₂—O, (CH₂)₂—O, or(CH₂)₃—O, In one embodiment, Y is O or CH₂—O, In one embodiment, Y is O.

In one embodiment, Y is C(O)NR₂₆, CH₂—C(O)NR₂₆, (CH₂)₂—C(O)NR₂₆,(CH₂)₃—C(O)NR₂₆, (CH₂)₄—C(O)NR₂₆, (CH₂)₅—C(O)NR₂₆, or (CH₂)₆—C(O)NR₂₆.In one embodiment, Y is C(O)R₂₆, CH₂—C(O)NR₂₆, (CH₂)₂—C(O)NR₂₆, or(CH₂)₃—C(O)NR₂₆. In one embodiment, Y is C(O)NR₂₆ or CH₂—C(O)NR₂₆. Inone embodiment, Y is C(O)NR₂₆.

In one embodiment, Y is NR₂₆C(O), CH₂—NR₂₆C(O), (CH₂)₂—NR₂₆C(O),(CH₂)₃—NR₂₆C(O), (CH₂)₄—NR₂₆C(O), (CH₂)₅—NR₂₆C(O), or (CH₂)₆—NR₂₆C(O).In one embodiment, Y is NR₂₆C(O), CH₂—NR₂₆C(O), (CH₂)₂—NR₂₆C(O), or(CH₂)₃—NR₂₆C(O). In one embodiment, Y is NR₂₆C(O) or CH₂—NR₂₆C(O). Inone embodiment, Y is NR₂₆C(O).

In one embodiment, R₂₆ is H. In one embodiment, R₂₆ is selected frommethyl, ethyl, propyl, butyl, i-butyl, t-butyl, pentyl, i-pentyl, andhexyl. In one embodiment, R₂₆ is C₁-C₃ alkyl selected from methyl,ethyl, and propyl.

In one embodiment, Y is NH, CH₂—NH, (CH₂)₂—NH, (CH₂)₃—NH, (CH₂)₄—NH,(CH₂)₅—NH, or (CH₂)₆—NH. In one embodiment, Y is NH, CH₂—NH, (CH₂)₂—NH,or (CH₂)₃—NH. In one embodiment, Y is NH or CH₂—NH. In one embodiment, Yis NH.

In one embodiment, Y is NR₂₇, CH₂—NR₂₇, (CH₂)₂—NR₂₇, (CH₂)₃—NR₂₇,(CH₂)₄—NR₂₇, (CH₂)₅—NR₂₇, or (CH₂)₆—NR₂₇. In one embodiment, Y is N R₂₇,CH₂—NR₂₇, (CH₂)₂—NR₂₇, or (CH₂)₃—NR₂₇. In one embodiment, Y is NR₂₇ orCH₂—NR₂₇. In one embodiment, Y is NR₂₇.

In one embodiment, R₂₇ is selected from methyl, ethyl, propyl, butyl,i-butyl, t-butyl, pentyl, i-pentyl, and hexyl. In one embodiment, R₂₇ isC₁-C₃ alkyl selected from methyl, ethyl, and propyl.

In one embodiment, R₂₇ is selected from C(O)-methyl, C(O)-ethyl,C(O)-propyl, C(O)-butyl, C(O)-i-butyl, C(O)-t-butyl, C(O)-pentyl,C(O)-i-pentyl, and C(O)-hexyl. In one embodiment, R₂₇ is C(O)—C₁-C₃alkyl selected from C(O)-methyl, C(O)-ethyl, and C(O)-propyl.

In one embodiment, R₂₈ is H.

In one embodiment, R₂₈ is C₁-C₃ alkyl selected from methyl, ethyl, andpropyl. In one embodiment, R₂₈ is methyl.

In one embodiment, q is 0.

In one embodiment, q is 1.

In one embodiment, q is 2.

In one embodiment, each R₂₉ is independently C₁-C₃ alkyl selected frommethyl, ethyl, and propyl.

In one embodiment, v is 0.

In one embodiment, v is 1.

In one embodiment, v is 2.

In one embodiment, v is 3.

In one embodiment, each R₃₁ is independently selected from halogen(e.g., F, Cl, Br, and I), OH, C₁-C₆ alkyl (e.g., methyl, ethyl, propyl,butyl, i-butyl, t-butyl, pentyl, i-pentyl, and hexyl), and C₁-C₆ alkoxy(e.g., methoxy, ethoxy, propoxy, butoxy, i-butoxy, t-butoxy, andpentoxy). In a further embodiment, each R₃₁ is independently selectedfrom F, Cl, OH, methyl, ethyl, propyl, butyl, i-butyl, t-butyl, methoxy,and ethoxy.

In one embodiment, R₃₀ is H, deuterium, or C₁-C₃ alkyl. In anotherembodiment, R₃₀ is H or C₁-C₃ alkyl. In a further embodiment, R₃₀ is inthe (S) or (R) configuration. In a further embodiment, R₃₀ is in the (S)configuration. In one embodiment, the compound comprises a racemicmixture of (S)-R₃₀ and (R)-R₃₀.

In one embodiment, R₃₀ is H.

In one embodiment, R₃₀ is deuterium.

In one embodiment, R₃₀ is C₁-C₃ alkyl selected from methyl, ethyl, andpropyl. In one embodiment, R₃₀ is methyl.

In one embodiment, R₃₀ is F or C₁. In a further embodiment, R₃₀ is inthe (S) or (R) configuration. In a further embodiment, R₃₀ is in the (R)configuration. In one embodiment, the compound comprises a racemicmixture of (S)-R₃₀ and (R)-R₃₀. In one embodiment, R₃₀ is F.

Any of the groups described herein for any of Y, Z₃, R₂₆, R₂₇, R₂₈, R₂₉,R₃₀, R₃₁, q and v can be combined with any of the groups describedherein for one or more of the remainder of Y, Z₃, R₂₆, R₂₇, R₂₈, R₂₉,R₃₀, R₃₁, q and v, and may further be combined with any of the groupsdescribed herein for the Linker.

For a Degron of Formula D1:

-   -   (1) In one embodiment, Z₃ is C(O) and Y is a bond.    -   (2) In one embodiment, Z₃ is C(O) and Y is NH.    -   (3) In one embodiment, Z₃ is C(O) and Y is (CH₂)₀₋₆—O. In a        further embodiment, Y is O.    -   (4) In one embodiment, Z₃ is C(O); Y is a bond; and q and v are        each 0.    -   (5) In one embodiment, Z₃ is C(O); Y is NH; and q and v are each        0.    -   (6) In one embodiment, Z₃ is C(O); Y is (CH₂)₀₋₆—O; and q and v        are each 0. In a further embodiment, Y is O.    -   (7) In one embodiment, Z₃ is C(O); Y is a bond; and R₂₈ is H.    -   (8) In one embodiment, Z₃ is C(O); Y is a bond; and R₂₈ is H.    -   (9) In one embodiment, Z₃ is C(O); Y is NH; and R₂₈ is H.    -   (10) In one embodiment, Z₃ is C(O); Y is NH; and R₃₀ is H.    -   (11) In one embodiment, Z₃ is C(O); Y is a bond; R₂₈ is H; and        R₃₀ is H.    -   (12) In one embodiment, Z₃ is C(O); Y is NH; R₂₈ is H; and R₃₀        is H.    -   (13) In one embodiment, Z₃ is C(O); Y is (CH₂)₀₋₆—O; and R₂₈        is H. In a further embodiment, Y is O.    -   (14) In one embodiment, Z₃ is C(O); Y is (CH₂)₀₋₆—O; and R₃₀        is H. In a further embodiment, Y is O.    -   (15) In one embodiment, Z₃ is C(O); Y is (CH₂)₀₋₆—O; R₂₈ is H;        and R₃₀ is H. In a further embodiment, Y is O.    -   (16) In one embodiment, q and v are each 0; and Y, Z₃, R₂₈, R₃₀,        and R₃₁ are each as defined in any of (1)-(3) and (7)-(15).    -   (17) In one embodiment, Z₃ is CH₂ and Y is a bond.    -   (18) In one embodiment, Z₃ is CH₂ and Y is NH.    -   (19) In one embodiment, Z₃ is CH₂ and Y is (CH₂)₀₋₆—O. In a        further embodiment, Y is O.    -   (20) In one embodiment, Z₃ is CH₂; Y is a bond; and q and v are        each 0.    -   (21) In one embodiment, Z₃ is CH₂; Y is NH; and q and v are each        0.    -   (22) In one embodiment, Z₃ is CH₂; Y is (CH₂)₀₋₆—O; and q and v        are each 0. In a further embodiment, Y is O.    -   (23) In one embodiment, Z₃ is CH₂; Y is a bond; and R₂₈ is H.    -   (24) In one embodiment, Z₃ is CH₂; Y is a bond; and R₃₀ is H.    -   (25) In one embodiment, Z₃ is CH₂; Y is NH; and R₂₈ is H.    -   (26) In one embodiment, Z₃ is CH₂; Y is NH; and R₃₀ is H.    -   (27) In one embodiment, Z₃ is CH₂; Y is a bond; R₂₈ is H; and        R₃₀ is H.    -   (28) In one embodiment, Z₃ is CH₂; Y is NH; R₂₈ is H; and R₃₀ is        H.    -   (29) In one embodiment, Z₃ is CH₂; Y is (CH₂)₀₋₆—O; and R₂₈        is H. In a further embodiment, Y is O.    -   (30) In one embodiment, Z₃ is CH₂; Y is (CH₂)₀₋₆—O; and R₃₀        is H. In a further embodiment, Y is O.    -   (31) In one embodiment, Z₃ is CH₂; Y is (CH₂)₀₋₆—O; R₂₈ is H;        and R₃₀ is H. In a further embodiment, Y is O.    -   (32) In one embodiment, q and v are each 0; and Y, Z₃, R₂₈, R₃₀,        and R₃₁ are each as defined in any of (17)-(19) and (23)-(31).

In one embodiment, the Degron is of Formula D1a, D1b, D1c, D1d, D1e,D1f, D1g, D1h, D1i, D1j, D1k, or D1l:

or an enantiomer, diastereomer, or stereoisomer thereof, wherein Y, R₂₉,R₃₁, q, and v are each as defined above in Formula D1, and can beselected from any moieties or combinations thereof described above.

In one embodiment, Y is a bond, O, or NH. In one embodiment, Y is abond. In one embodiment, Y is O. In one embodiment, Y is NH.

In one embodiment, the Degron is of Formula D2:

or an enantiomer, diastereomer, or stereoisomer thereof, wherein:

each R₃₂ is independently C₁-C₃ alkyl;

q′ is 0, 1, 2, 3 or 4; and

R₃₃ is H or C₁-C₃ alkyl,

wherein the Degron is covalently bonded to another moiety (e.g., acompound, or a Linker) via

In one embodiment, q′ is 0.

In one embodiment, q′ is 1.

In one embodiment, q′ is 2.

In one embodiment, q′ is 3.

In one embodiment, each R₃₂ is independently C₁-C₃ alkyl selected frommethyl, ethyl, and propyl.

In one embodiment, R₃₃ is methyl, ethyl, or propyl. In one embodiment,R₃₃ is methyl.

In one embodiment, the Degron is of Formula D2a:

or an enantiomer, diastereomer, or stereoisomer thereof, wherein:

each R₃₂ is independently C₁-C₃ alkyl;

q′ is 0, 1, 2, 3 or 4; and

R₃₃ is H or C₁-C₃ alkyl,

wherein the Degron is covalently bonded to another moiety (e.g., acompound, or a Linker) via

In one embodiment, q′ is 0.

In one embodiment, q′ is 1.

In one embodiment, q′ is 2.

In one embodiment, q′ is 3.

In one embodiment, each R₃₂ is independently C₁-C₃ alkyl selected frommethyl, ethyl, and propyl.

In one embodiment, R₃₃ is methyl, ethyl, or propyl. In one embodiment,R₃₃ is methyl.

In one embodiment, the Degron is of Formula D2b:

or an enantiomer, diastereomer, or stereoisomer thereof, wherein:

each R₃₂ is independently C₁-C₃ alkyl;

q′ is 0, 1, 2, 3 or 4; and

R₃₃ is H or C₁-C₃ alkyl,

wherein the Degron is covalently bonded to another moiety (e.g., acompound, or a Linker) via

In one embodiment, q′ is 0.

In one embodiment, q′ is 1.

In one embodiment, q′ is 2.

In one embodiment, q′ is 3.

In one embodiment, each R₃₂ is independently C₁-C₃ alkyl selected frommethyl, ethyl, and propyl.

In one embodiment, R₃₃ is methyl, ethyl, or propyl. In one embodiment,R₃₃ is methyl.

In one embodiment, the Degron is of Formula D2c:

or an enantiomer, diastereomer, or stereoisomer thereof, wherein:wherein the Degron is covalently bonded to another moiety (e.g., acompound, or a Linker) via

In one embodiment, the Degron is of Formula D2d:

or an enantiomer, diastereomer, or stereoisomer thereof, wherein:wherein the Degron is covalently bonded to another moiety (e.g., acompound, or a Linker) via

Linker

The Linker is a bond, a carbon chain, carbocyclic ring, or heterocyclicring that serves to link a Targeting Ligand with a Degron. In oneembodiment, the carbon chain optionally comprises one, two, three, ormore heteroatoms selected from N, O, and S. In one embodiment, thecarbon chain comprises only saturated chain carbon atoms. In oneembodiment, the carbon chain optionally comprises two or moreunsaturated chain carbon atoms (e.g., C═C or C≡C). In one embodiment,one or more chain carbon atoms in the carbon chain are optionallysubstituted with one or more substituents (e.g., oxo, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₁-C₃ alkoxy, OH, halogen, NH₂, NH(C₁-C₃ alkyl),N(C₁-C₃ alkyl)₂, CN, C₃-C₈ cycloalkyl, heterocyclyl, phenyl, andheteroaryl).

In one embodiment, the Linker comprises at least 5 chain atoms (e.g., C,O, N, and S). In one embodiment, the Linker comprises less than 25 chainatoms (e.g., C, O, N, and S). In one embodiment, the Linker comprisesless than 20 chain atoms (e.g., C, O, N, and S). In one embodiment, theLinker comprises 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, or 24 chain atoms (e.g., C, O, N, and S). In oneembodiment, the Linker comprises 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, or 24 chain atoms (e.g., C, O, N, andS). In one embodiment, the Linker comprises 5, 7, 9, 11, 13, 15, 17, or19 chain atoms (e.g., C, O, N, and S). In one embodiment, the Linkercomprises 5, 7, 9, or 11 chain atoms (e.g., C, O, N, and S). In oneembodiment, the Linker comprises 11, 13, 15, 17, or 19 chain atoms(e.g., C, O, N, and S). In one embodiment, the Linker comprises 11, 13,15, 17, 19, 21, or 23 chain atoms (e.g., C, O, N, and S). In oneembodiment, the Linker comprises 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24chain atoms (e.g., C, O, N, and S). In one embodiment, the Linkercomprises 6, 8, 10, 12, 14, 16, 18, or 20 chain atoms (e.g., C, O, N,and S). In one embodiment, the Linker comprises 6, 8, 10, or 12 chainatoms (e.g., C, O, N, and S). In one embodiment, the Linker comprises12, 14, 16, 18, or 20 chain atoms (e.g., C, O, N, and S).

In one embodiment, the Linker comprises from 11 to 19 chain atoms (e.g.,C, O, N, and S).

In one embodiment, the Linker is a carbon chain optionally substitutedwith non-bulky substituents (e.g., oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₁-C₃ alkoxy, OH, halogen, NH₂, NH(C₁-C₃ alkyl), N(C₁-C₃alkyl)₂, and CN). In one embodiment, the non-bulky substitution islocated on the chain carbon atom proximal to the Degron (i.e., thecarbon atom is separated from the carbon atom to which the Degron isbonded by at least 3, 4, or 5 chain atoms in the Linker). In oneembodiment, the non-bulky substitution is located on the chain carbonatom proximal to the Targeting Ligand (i.e., the carbon atom isseparated from the carbon atom to which the Degron is bonded by at least3, 4, or 5 chain atoms in the Linker).

In one embodiment, the Linker is of Formula L1:

or an enantiomer, diastereomer, or stereoisomer thereof, wherein

p1 is an integer selected from 0 to 12;

p2 is an integer selected from 0 to 12;

p3 is an integer selected from 1 to 6;

each W is independently absent, CH₂, O, S, or NR₂₄;

Z₁ is absent, C(O), CH₂, O, (CH₂)_(j)NR₂₄, O(CH₂)_(j)C(O)NR₂₄, C(O)NR₂₄,(CH₂)_(j)C(O)NR₂₄, NR₂₄C(O), (CH₂)_(j)NR₂₄C(O),(CH₂)_(k)NR₂₄(CH₂)_(j)C(O)NR₂₄, or NR₂₄(CH₂)_(j)C(O)NR₂₄;

each R₂₄ is independently H or C₁-C₃ alkyl;

j is 1, 2, or 3;

k is 1, 2, or 3; and

Q₁ is absent, C(O), NHC(O)CH₂, OCH₂C(O), or O(CH₂)₁₋₂;

wherein the Linker is covalently bonded to a Degron via the

next to Q₁, and covalently bonded to a Targeting Ligand via the

next to Z₁.

In one embodiment, the total number of chain atoms in the Linker is lessthan 30. In a further embodiment, the total number of chain atoms in theLinker is less than 20.

For a Linker of Formula L1:

-   (1) In one embodiment, p1 is an integer selected from 0 to 10.-   (2) In one embodiment, p1 is an integer selected from 1 to 10.-   (3) In one embodiment, p1 is selected from 1, 2, 3, 4, 5, and 6.-   (4) In one embodiment, p1 is 0, 1, 3, or 5.-   (5) In one embodiment, p1 is 0, 1, 2, or 3.-   (6) In one embodiment, p1 is 0.-   (7) In one embodiment, p1 is 1.-   (8) In one embodiment, p1 is 2.-   (9) In one embodiment, p1 is 3.-   (10) In one embodiment, p1 is 4.-   (11) In one embodiment, p1 is 5.-   (12) In one embodiment, p2 is an integer selected from 0 to 10.-   (13) In one embodiment, p2 is selected from 0, 1, 2, 3, 4, 5, and 6.-   (14) In one embodiment, p2 is 0, 1, 2, or 3.-   (15) In one embodiment, p2 is 0.-   (16) In one embodiment, p2 is 1.-   (17) In one embodiment, p2 is 2.-   (18) In one embodiment, p2 is 3.-   (19) In one embodiment, p3 is an integer selected from 1 to 5.-   (20) In one embodiment, p3 is 2, 3, 4, or 5.-   (21) In one embodiment, p3 is 0, 1, 2, or 3.-   (22) In one embodiment, p3 is 0.-   (23) In one embodiment, p3 is 1.-   (24) In one embodiment, p3 is 2.-   (25) In one embodiment, p3 is 3.-   (26) In one embodiment, p3 is 4.-   (27) In one embodiment, at least one W is CH₂.-   (28) In one embodiment, at least one W is O.-   (29) In one embodiment, at least one W is S.-   (30) In one embodiment, at least one W is NH.-   (31) In one embodiment, at least one W is NR₂₄; and each R₂₄ is    independently C₁-C₃ alkyl selected from methyl, ethyl, and propyl.-   (32) In one embodiment, each W is O.-   (33) In one embodiment, each W is CH₂.-   (34) In one embodiment, j is 1, 2, or 3.-   (35) In one embodiment, j is 1.-   (36) In one embodiment, j is 2.-   (37) In one embodiment, j is 3.-   (38) In one embodiment, j is 2 or 3.-   (39) In one embodiment, j is 1 or 2.-   (40) In one embodiment, k is 1, 2, or 3.-   (41) In one embodiment, k is 1.-   (42) In one embodiment, k is 2.-   (43) In one embodiment, k is 3.-   (44) In one embodiment, k is 2 or 3.-   (45) In one embodiment, k is 1 or 2.-   (46) In one embodiment, Q₁ is absent.-   (47) In one embodiment, Q₁ is NHC(O)CH₂.-   (48) In one embodiment, Q₁ is O(CH₂)₁₋₂.-   (49) In one embodiment, Q₁ is OCH₂.-   (50) In one embodiment, Q₁ is OCH₂CH₂.-   (51) In one embodiment, Q₁ is OCH₂C(O).-   (52) In one embodiment, Q₁ is C(O).-   (53) In one embodiment, Z₁ is absent.-   (54) In one embodiment, Z₁ is O(CH₂)_(j)C(O)NR₂₄; and R₂₄ is C₁-C₃    alkyl selected from methyl, ethyl, and propyl.-   (55) In one embodiment, Z₁ is O(CH₂)_(j)C(O)NR₂₄; and R₂₄ is H.-   (56) In one embodiment, Z₁ is O(CH₂)_(j)C(O)NR₂₄; R₂₄ is C₁-C₃ alkyl    selected from methyl, ethyl, and propyl; and j is 1.-   (57) In one embodiment, Z₁ is O(CH₂)_(j)C(O)NR₂₄; R₂₄ is H; and j is    1.-   (58) In one embodiment, Z₁ is O(CH₂)_(j)C(O)NR₂₄; R₂₄ is C₁-C₃ alkyl    selected from methyl, ethyl, and propyl; and j is 2.-   (59) In one embodiment, Z₁ is O(CH₂)_(j)C(O)NR₂₄; R₂₄ is H; and j is    2.-   (60) In one embodiment, Z₁ is O(CH₂)_(j)C(O)NR₂₄; R₂₄ is C₁-C₃ alkyl    selected from methyl, ethyl, and propyl; and j is 3.-   (61) In one embodiment, Z₁ is O(CH₂)_(j)C(O)NR₂₄; and R₂₄ is H; and    j is 3.-   (62) In one embodiment, Z₁ is C(O)NR₂₄; and R₂₄ is H.-   (63) In one embodiment, Z₁ is C(O)NR₂₄; and R₂₄ is C₁-C₃ alkyl    selected from methyl, ethyl, and propyl.-   (64) In one embodiment, Z₁ is (CH₂)_(j)C(O)NR₂₄; and R₂₄ is H.-   (65) In one embodiment, Z₁ is (CH₂)_(j)C(O)NR₂₄; and R₂₄ is C₁-C₃    alkyl selected from methyl, ethyl, and propyl.-   (66) In one embodiment, Z₁ is (CH₂)_(j)C(O)NR₂₄; R₂₄ is H; and j is    1.-   (67) In one embodiment, Z₁ is (CH₂)_(j)C(O)NR₂₄; R₂₄ is C₁-C₃ alkyl    selected from methyl, ethyl, and propyl; and j is 1-   (68) In one embodiment, Z₁ is (CH₂)_(j)C(O)NR₂₄; R₂₄ is H; and j is    2.-   (69) In one embodiment, Z₁ is (CH₂)_(j)C(O)NR₂₄; R₂₄ is C₁-C₃ alkyl    selected from methyl, ethyl, and propyl; and j is 2.-   (70) In one embodiment, Z₁ is (CH₂)_(j)C(O)NR₂₄; R₂₄ is H; and j is    3.-   (71) In one embodiment, Z₁ is (CH₂)_(j)C(O)NR₂₄; R₂₄ is C₁-C₃ alkyl    selected from methyl, ethyl, and propyl; and j is 3.-   (72) In one embodiment, Z₁ is NR₂₄C(O); and R₂₄ is H.-   (73) In one embodiment, Z₁ is NR₂₄C(O); and R₂₄ is C₁-C₃ alkyl    selected from methyl, ethyl, and propyl.-   (74) In one embodiment, Z₁ is (CH₂)_(j)NR₂₄C(O); and R₂₄ is H.-   (75) In one embodiment, Z₁ is (CH₂)_(j)NR₂₄C(O); and R₂₄ is C₁-C₃    alkyl selected from methyl, ethyl, and propyl.-   (76) In one embodiment, Z₁ is (CH₂)_(j)NR₂₄C(O); R₂₄ is H; and j is    1.-   (77) In one embodiment, Z₁ is (CH₂)_(j)NR₂₄C(O); R₂₄ is C₁-C₃ alkyl    selected from methyl, ethyl, and propyl; and j is 1-   (78) In one embodiment, Z₁ is (CH₂)_(j)NR₂₄C(O); R₂₄ is H; and j is    2.-   (79) In one embodiment, Z₁ is (CH₂)_(j)NR₂₄C(O); R₂₄ is C₁-C₃ alkyl    selected from methyl, ethyl, and propyl; and j is 2.-   (80) In one embodiment, Z₁ is (CH₂)_(j)NR₂₄C(O); R₂₄ is H; and j is    3.-   (81) In one embodiment, Z₁ is (CH₂)_(j)NR₂₄C(O); R₂₄ is C₁-C₃ alkyl    selected from methyl, ethyl, and propyl; and j is 3.-   (82) In one embodiment, Z₁ is (CH₂)_(k)NR₂₄(CH₂)_(j)C(O)NR₂₄; and    each R₂₄ is independently H or C₁-C₃ alkyl selected from methyl,    ethyl, and propyl.-   (83) In one embodiment, Z₁ is (CH₂)_(k)NR₂₄(CH₂)_(j)C(O)NR₂₄; and    one of R₂₄ is H and one of R₂₄ is C₁-C₃ alkyl selected from methyl,    ethyl, and propyl. In one embodiment, Z₁ is    (CH₂)_(k)NR₂₄(CH₂)_(j)C(O)NH.-   (84) In one embodiment, Z₁ is (CH₂)_(k)NR₂₄(CH₂)_(j)C(O)NR₂₄; each    R₂₄ is independently H or C₁-C₃ alkyl selected from methyl, ethyl,    and propyl; and j is 1.-   (85) In one embodiment, Z₁ is (CH₂)_(k)NR₂₄(CH₂)_(j)C(O)NR₂₄; each    R₂₄ is independently H or C₁-C₃ alkyl selected from methyl, ethyl,    and propyl; and k is 1.-   (86) In one embodiment, Z₁ is (CH₂)_(k)NR₂₄(CH₂)_(j)C(O)NR₂₄; each    R₂₄ is independently H or C₁-C₃ alkyl selected from methyl, ethyl,    and propyl; j is 1; and k is 1.-   (87) In one embodiment, Z₁ is (CH₂)_(k)NR₂₄(CH₂)_(j)C(O)NR₂₄; one of    R₂₄ is H and one of R₂₄ is C₁-C₃ alkyl selected from methyl, ethyl,    and propyl; and j is 1. In one embodiment, Z₁ is    (CH₂)_(k)NR₂₄(CH₂)C(O)NH.-   (88) In one embodiment, Z₁ is (CH₂)_(k)NR₂₄(CH₂)_(j)C(O)NR₂₄; one of    R₂₄ is H and one of R₂₄ is C₁-C₃ alkyl selected from methyl, ethyl,    and propyl; and k is 1. In one embodiment, Z₁ is    (CH₂)NR₂₄(CH₂)_(j)C(O)NH.-   (89) In one embodiment, Z₁ is (CH₂)_(k)NR₂₄(CH₂)_(j)C(O)NR₂₄; one of    R₂₄ is H and one of R₂₄ is C₁-C₃ alkyl selected from methyl, ethyl,    and propyl; j is 1; and k is 1. In one embodiment, Z₁ is    (CH₂)NR₂₄(CH₂)C(O)NH. In one embodiment, Z₁ is    (CH₂)N(CH₃)(CH₂)C(O)NH.-   (90) In one embodiment, Z₁ is (CH₂)_(k)NR₂₄(CH₂)_(j)C(O)NR₂₄; each    R₂₄ is independently H or C₁-C₃ alkyl selected from methyl, ethyl,    and propyl; and j is 2.-   (91) In one embodiment, Z₁ is (CH₂)_(k)NR₂₄(CH₂)_(j)C(O)NR₂₄; each    R₂₄ is independently H or C₁-C₃ alkyl selected from methyl, ethyl,    and propyl; and k is 2.-   (92) In one embodiment, Z₁ is (CH₂)_(k)NR₂₄(CH₂)_(j)C(O)NR₂₄; one of    R₂₄ is H and one of R₂₄ is C₁-C₃ alkyl selected from methyl, ethyl,    and propyl; and j is 2. In one embodiment, Z₁ is    (CH₂)_(k)NR₂₄(CH₂)₂C(O)NH.-   (93) In one embodiment, Z₁ is (CH₂)_(k)NR₂₄(CH₂)_(j)C(O)NR₂₄; one of    R₂₄ is H and one of R₂₄ is C₁-C₃ alkyl selected from methyl, ethyl,    and propyl; and k is 2. In one embodiment, Z₁ is    (CH₂)₂NR₂₄(CH₂)_(j)C(O)NH.-   (94) In one embodiment, Z₁ is (CH₂)_(k)NR₂₄(CH₂)_(j)C(O)NR₂₄; each    R₂₄ is independently H or C₁-C₃ alkyl selected from methyl, ethyl,    and propyl; and j is 3.-   (95) In one embodiment, Z₁ is (CH₂)_(k)NR₂₄(CH₂)_(j)C(O)NR₂₄; each    R₂₄ is independently H or C₁-C₃ alkyl selected from methyl, ethyl,    and propyl; and k is 3.-   (96) In one embodiment, Z₁ is (CH₂)_(k)NR₂₄(CH₂)_(j)C(O)NR₂₄; one of    R₂₄ is H and one of R₂₄ is C₁-C₃ alkyl selected from methyl, ethyl,    and propyl; and j is 3. In one embodiment, Z₁ is    (CH₂)_(k)NR₂₄(CH₂)₃C(O)NH.-   (97) In one embodiment, Z₁ is (CH₂)_(k)NR₂₄(CH₂)_(j)C(O)NR₂₄; one of    R₂₄ is H and one of R₂₄ is C₁-C₃ alkyl selected from methyl, ethyl,    and propyl; and k is 3. In one embodiment, Z₁ is    (CH₂)₃NR₂₄(CH₂)_(j)C(O)NH.-   (98) In one embodiment, Z₁ is NR₂₄(CH₂)_(j)C(O)NR₂₄; and each R₂₄ is    independently H or C₁-C₃ alkyl selected from methyl, ethyl, and    propyl.-   (99) In one embodiment, Z₁ is NR₂₄(CH₂)_(j)C(O)NR₂₄; and each R₂₄ is    H.-   (100) In one embodiment, Z₁ is NR₂₄(CH₂)_(j)C(O)NR₂₄; one of R₂₄ is    H and one of R₂₄ is C₁-C₃ alkyl selected from methyl, ethyl, and    propyl; and j is 1.-   (101) In one embodiment, Z₁ is NR₂₄(CH₂)_(j)C(O)NR₂₄; R₂₄ is H; and    j is 1.-   (102) In one embodiment, Z₁ is NR₂₄(CH₂)_(j)C(O)NR₂₄; one of R₂₄ is    H and one of R₂₄ is C₁-C₃ alkyl selected from methyl, ethyl, and    propyl; and j is 2.-   (103) In one embodiment, Z₁ is NR₂₄(CH₂)_(j)C(O)NR₂₄; R₂₄ is H; and    j is 2.-   (104) In one embodiment, Z₁ is NR₂₄(CH₂)_(j)C(O)NR₂₄; one of R₂₄ is    H and one of R₂₄ is C₁-C₃ alkyl selected from methyl, ethyl, and    propyl; and j is 3.-   (105) In one embodiment, Z₁ is absent and p3 is 1.-   (106) In one embodiment, Z₁ is absent and p3 is 2.-   (107) In one embodiment, Z₁ is absent and p3 is 3.-   (108) In one embodiment, Z₁ is absent, p3 is 1, and p1 is 1-8.-   (109) In one embodiment, Z₁ is absent, p3 is 1, and p1 is 1.-   (110) In one embodiment, Z₁ is absent, p3 is 1, and p1 is 2.-   (111) In one embodiment, Z₁ is absent, p3 is 1, and p1 is 3.-   (112) In one embodiment, Z₁ is absent, p3 is 1, and p1 is 4.-   (113) In one embodiment, Z₁ is absent, p3 is 1, and p1 is 5.-   (114) In one embodiment, Z₁ is absent, p3 is 1, and p1 is 6.-   (115) In one embodiment, Z₁ is absent, p3 is 1, and p1 is 7.-   (116) In one embodiment, Z₁ is absent, p3 is 1, and p1 is 8.-   (117) In one embodiment, Z₁ is absent, p3 is 1, and W is O.-   (118) In one embodiment, Z₁ is absent, p3 is 1, p1 is 1, and W is O.-   (119) In one embodiment, Z₁ is absent, p3 is 1, p1 is 2, and W is O.-   (120) In one embodiment, Z₁ is absent, p3 is 1, p1 is 3, and W is O.-   (121) In one embodiment, Z₁ is absent, p3 is 1, p1 is 4, and W is O.-   (122) In one embodiment, Z₁ is absent, p3 is 1, p1 is 5, and W is O.-   (123) In one embodiment, Z₁ is absent, p3 is 1, p1 is 6, and W is O.-   (124) In one embodiment, Z₁ is absent, p3 is 1, p1 is 7, and W is O.-   (125) In one embodiment, Z₁ is absent, p3 is 1, p1 is 8, and W is O.-   (126) In one embodiment, Z₁ is absent, p3 is 1, p1 is 1, and W is    CH₂.-   (127) In one embodiment, Z₁ is absent, p3 is 1, p1 is 2, and W is    CH₂.-   (128) In one embodiment, Z₁ is absent, p3 is 1, p1 is 3, and W is    CH₂.-   (129) In one embodiment, Z₁ is absent, p3 is 1, p1 is 4, and W is    CH₂.-   (130) In one embodiment, Z₁ is absent, p3 is 1, p1 is 5, and W is    CH₂.-   (131) In one embodiment, Z₁ is absent, p3 is 1, p1 is 6, and W is    CH₂.-   (132) In one embodiment, Z₁ is absent, p3 is 1, p1 is 7, and W is    CH₂.-   (133) In one embodiment, Z₁ is absent, p3 is 1, p1 is 8, and W is    CH₂.-   (134) In one embodiment, Z₁ is absent, p3 is 2, p1 is 1, and W is O.-   (135) In one embodiment, Z₁ is absent, p3 is 2, p1 is 2, and W is O.-   (136) In one embodiment, Z₁ is absent, p3 is 2, p1 is 3, and W is O.-   (137) In one embodiment, Z₁ is absent, p3 is 2, p1 is 4, and W is O.-   (138) In one embodiment, Z₁ is absent, p3 is 2, p1 is 5, and W is O.-   (139) In one embodiment, Z₁ is absent, p3 is 2, p1 is 6, and W is O.-   (140) In one embodiment, Z₁ is absent, p3 is 2, p1 is 7, and W is O.-   (141) In one embodiment, Z₁ is absent, p3 is 2, p1 is 8, and W is O.-   (142) In one embodiment, Z₁ is absent, p3 is 2, p1 is 1, and W is    CH₂.-   (143) In one embodiment, Z₁ is absent, p3 is 2, p1 is 2, and W is    CH₂.-   (144) In one embodiment, Z₁ is absent, p3 is 2, p1 is 3, and W is    CH₂.-   (145) In one embodiment, Z₁ is absent, p3 is 2, p1 is 4, and W is    CH₂.-   (146) In one embodiment, Z₁ is absent, p3 is 2, p1 is 5, and W is    CH₂.-   (147) In one embodiment, Z₁ is absent, p3 is 2, p1 is 6, and W is    CH₂.-   (148) In one embodiment, Z₁ is absent, p3 is 2, p1 is 7, and W is    CH₂.-   (149) In one embodiment, Z₁ is absent, p3 is 2, p1 is 8, and W is    CH₂.-   (150) In one embodiment, Z₁ is absent, p3 is 3, p1 is 1, and W is O.-   (151) In one embodiment, Z₁ is absent, p3 is 3, p1 is 2, and W is O.-   (152) In one embodiment, Z₁ is absent, p3 is 3, p1 is 3, and W is O.-   (153) In one embodiment, Z₁ is absent, p3 is 3, p1 is 4, and W is O.-   (154) In one embodiment, Z₁ is absent, p3 is 3, p1 is 5, and W is O.-   (155) In one embodiment, Z₁ is absent, p3 is 3, p1 is 6, and W is O.-   (156) In one embodiment, Z₁ is absent, p3 is 3, p1 is 7, and W is O.-   (157) In one embodiment, Z₁ is absent, p3 is 3, p1 is 8, and W is O.-   (158) In one embodiment, Z₁ is absent, p3 is 3, p1 is 1, and W is    CH₂.-   (159) In one embodiment, Z₁ is absent, p3 is 3, p1 is 2, and W is    CH₂.-   (160) In one embodiment, Z₁ is absent, p3 is 3, p1 is 3, and W is    CH₂.-   (161) In one embodiment, Z₁ is absent, p3 is 3, p1 is 4, and W is    CH₂.-   (162) In one embodiment, Z₁ is absent, p3 is 3, p1 is 5, and W is    CH₂.-   (163) In one embodiment, Z₁ is absent, p3 is 3, p1 is 6, and W is    CH₂.-   (164) In one embodiment, Z₁ is absent, p3 is 3, p1 is 7, and W is    CH₂.-   (165) In one embodiment, Z₁ is absent, p3 is 3, p1 is 8, and W is    CH₂.-   (166) In one embodiment, p1, Z₁, p3, and W are each as defined,    where applicable, in any one of (1)-(165), and p2 is 0.-   (167) In one embodiment, p1, Z₁, p3, and W are each as defined,    where applicable, in any one of (1)-(165), and p2 is 1.-   (168) In one embodiment, p1, Z₁, p3, and W are each as defined,    where applicable, in any one of (1)-(165), and p2 is 2.-   (169) In one embodiment, p1, Z₁, p3, p2, and W are each as defined,    where applicable, in any one of (1)-(168), and Q₁ is absent.-   (170) In one embodiment, p1, Z₁, p3, p2, and W are each as defined,    where applicable, in any one of (1)-(168), and Q₁ is NHC(O)CH₂.-   (171) In one embodiment, p1, Z₁, p3, p2, and W are each as defined,    where applicable, in any one of (1)-(168), and Q₁ is O(CH₂)₁₋₂.-   (172) In one embodiment, p1, Z₁, p3, p2, and W are each as defined,    where applicable, in any one of (1)-(168), and Q₁ is O(CH₂).-   (173) In one embodiment, p1, Z₁, p3, p2, and W are each as defined,    where applicable, in any one of (1)-(168), and Q₁ is O(CH₂CH₂).-   (174) In one embodiment, p1, Z₁, p3, p2, and W are each as defined,    where applicable, in any one of (1)-(168), and Q₁ is C(O).-   (175) In one embodiment, p1, Z₁, p3, p2, and W are each as defined,    where applicable, in any one of (1)-(168), and Q₁ is OCH₂C(O).

In one embodiment, the Linker-Targeting Ligand (TL) has the structureselected from Table L:

TABLE L

(L1a)

(L1b)

(L1c)

(L1d)

(L1e)

(L1f)

(L1g)

(L1h)

(Lli)

(L1j)

(L1k)

(L1l)

(L1m)

(L1n)

(L1o)wherein Z₁, W, Q₁, TL, p1, and p3 are each as described above.

In one embodiment, the present application relates to the Degron-Linker(DL), wherein the Degron is of Formula D1, and the Linker is selectedfrom L1a-L1o. In one embodiment, the present application relates to theDegron-Linker (DL), wherein the Degron is of Formula D1, and the Linkeris selected from L1a. In one embodiment, the Degron is of Formula D1,and the Linker is selected from L1b-L1d. In one embodiment, the Degronis of Formula D1, and the Linker is selected from L1e-L1g. In oneembodiment, the Degron is of Formula D1, and the Linker is L1h-L1j. Inone embodiment, the Degron is of Formula D1, and the Linker is L1p orL1q. In one embodiment, the Degron is of Formula D1, and the Linker isL1a, L1b, Lie, L1h, L1k, L1l or L1o. In one embodiment, the Degron is ofFormula D1, and the Linker is L1c, L1d, L1f, L1g, L1i, L1j, L1m, or L1n.In one embodiment, the Degron is of Formula D1, and the Linker is L1k.In one embodiment, the Degron is of Formula D1, and the Linker is L1l orL1o.

In one embodiment, the Degron is of Formula D1, and the Linker is L1c orL1d. In one embodiment, the Degron is of Formula D1, and the Linker isL1f or L1g. In one embodiment, the Degron is of Formula D1, and theLinker is L1i or L1j. In one embodiment, the Degron is of Formula D1,and the Linker is L1m or L1n.

In one embodiment, the present application relates to the Degron-Linker(DL), wherein the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f,D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is selected fromL1a-L1o. In one embodiment, the present application relates to theDegron-Linker (DL), wherein the Degron is of Formula D1a, D1b, D1c, D1d,D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is selectedfrom L1a. In one embodiment, the Degron is of Formula D1a, D1b, D1c,D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker isselected from L1b-L1d. In one embodiment, the Degron is of Formula D1a,D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linkeris selected from L1e-L1g. In one embodiment, the Degron is of FormulaD1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and theLinker is L1h-L1j. In one embodiment, the Degron is of Formula D1a, D1b,D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker isL1p or L1q. In one embodiment, the Degron is of Formula D1a, D1b, D1c,D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is L1a,L1b, L1e, L1h, L1k, L1l or L1o. In one embodiment, the Degron is ofFormula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l,and the Linker is L1c, L1d, L1f, L1g, L1i, L1j, L1m, or L1n. In oneembodiment, the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g,D1h, D1i, D1j, D1k, or D1l, and the Linker is L1k. In one embodiment,the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i,D1j, D1k, or D1l, and the Linker is L1l or L1o. In one embodiment, theDegron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j,D1k, or D1l, and the Linker is L1c or L1d. In one embodiment, the Degronis of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, orD1l, and the Linker is L1f or L1g. In one embodiment, the Degron is ofFormula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l,and the Linker is L1i or L1j. In one embodiment, the Degron is ofFormula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D11,and the Linker is L1m or L1n.

In one embodiment, the present application relates to the Degron-Linker(DL), wherein the Degron is of Formula D2, and the Linker is selectedfrom L1a-L1o. In one embodiment, the present application relates to theDegron-Linker (DL), wherein the Degron is of Formula D2, and the Linkeris selected from L1a. In one embodiment, the Degron is of Formula D2,and the Linker is selected from L1b-L1d. In one embodiment, the Degronis of Formula D2, and the Linker is selected from L1e-L1g. In oneembodiment, the Degron is of Formula D2, and the Linker is L1h-L1j. Inone embodiment, the Degron is of Formula D2, and the Linker is L1p orL1q. In one embodiment, the Degron is of Formula D2, and the Linker isL1a, L1b, L1e, L1h, L1k, L1l or L1o. In one embodiment, the Degron is ofFormula D2, and the Linker is L1c, L1d, L1f, L1g, L1i, L1j, L1m, or L1n.In one embodiment, the Degron is of Formula D2, and the Linker is L1k.In one embodiment, the Degron is of Formula D2, and the Linker is L1l orL1o. In one embodiment, the Degron is of Formula D2, and the Linker isL1c or L1d. In one embodiment, the Degron is of Formula D2, and theLinker is L1f or L1g. In one embodiment, the Degron is of Formula D2,and the Linker is L1i or L1j. In one embodiment, the Degron is ofFormula D2, and the Linker is L1m or L1n.

In one embodiment, the present application relates to the Degron-Linker(DL), wherein the Degron is of Formula D2a or D2b, and the Linker isselected from L1a-L1o. In one embodiment, the present applicationrelates to the Degron-Linker (DL), wherein the Degron is of Formula D2aor D2b, and the Linker is selected from L1a. In one embodiment, theDegron is of Formula D2a or D2b, and the Linker is selected fromL1b-L1d. In one embodiment, the Degron is of Formula D2a or D2b, and theLinker is selected from L1e-L1g. In one embodiment, the Degron is ofFormula D2a or D2b, and the Linker is L1h-L1j. In one embodiment, theDegron is of Formula D2a or D2b, and the Linker is L1p or L1q. In oneembodiment, the Degron is of Formula D2a or D2b, and the Linker is L1a,L1b, L1e, L1h, L1k, L1l or L1o. In one embodiment, the Degron is ofFormula D2a or D2b, and the Linker is L1c, L1d, L1f, L1g, L1i, L1j, L1m,or L1n. In one embodiment, the Degron is of Formula D2a or D2b, and theLinker is L1k. In one embodiment, the Degron is of Formula D2a or D2b,and the Linker is L1l or L1o. In one embodiment, the Degron is ofFormula D2a or D2b, and the Linker is L1c or L1d. In one embodiment, theDegron is of Formula D2a or D2b, and the Linker is L1f or L1g. In oneembodiment, the Degron is of Formula D2a or D2b, and the Linker is L1ior L1j. In one embodiment, the Degron is of Formula D2a or D2b, and theLinker is L1m or L1n.

In one embodiment, the present application relates to the Degron-Linker(DL), wherein the Degron is of Formula D2c or D2d, and the Linker isselected from L1a-L1o. In one embodiment, the present applicationrelates to the Degron-Linker (DL), wherein the Degron is of Formula D2cor D2d, and the Linker is selected from L1a. In one embodiment, theDegron is of Formula D2c or D2d, and the Linker is selected fromL1b-L1d. In one embodiment, the Degron is of Formula D2c or D2d, and theLinker is selected from L1e-L1g. In one embodiment, the Degron is ofFormula D2c or D2d, and the Linker is L1h-L1j. In one embodiment, theDegron is of Formula D2c or D2d, and the Linker is L1p or L1q. In oneembodiment, the Degron is of Formula D2c or D2d, and the Linker is L1a,L1b, L1e, L1h, L1k, L1l or L1o. In one embodiment, the Degron is ofFormula D2c or D2d, and the Linker is L1c, L1d, L1f, L1g, L1i, L1j, L1m,or L1n. In one embodiment, the Degron is of Formula D2c or D2d, and theLinker is L1k. In one embodiment, the Degron is of Formula D2c or D2d,and the Linker is L1l or L1o. In one embodiment, the Degron is ofFormula D2c or D2d, and the Linker is L1c or L1d. In one embodiment, theDegron is of Formula D2c or D2d, and the Linker is L1f or L1g. In oneembodiment, the Degron is of Formula D2c or D2d, and the Linker is L1ior L1j. In one embodiment, the Degron is of Formula D2c or D2d, and theLinker is L1m or L1n.

In one embodiment, the Linker is of Formula L2:

or an enantiomer, diastereomer, or stereoisomer thereof, wherein

p4 and p4′ are each independently an integer selected from 0 to 12;

p5 is an integer selected from 0 to 12;

p6 is an integer selected from 1 to 6;

each W₁ is independently absent, CH₂, O, S, or NR₂₅;

W₂ is NR₂₅C(O)(CH₂)₀₋₂ or

each W₃ is independently absent, CH₂, O, S, or NR₂₅;

Z₂ is absent, C(O), CH₂, O, (CH₂)_(j1)NR₂₅, O(CH₂)_(j1)C(O)NR₂₅,C(O)NR₂₅, (CH₂)_(j1)C(O)NR₂₅, NR₂₅C(O), (CH₂)_(j1)NR₂₅C(O),(CH₂)_(k1)NR₂₅(CH₂)_(j1)C(O)NR₂₅, or NR₂₅(CH₂)_(j1)C(O)NR₂₅;

each R₂₅ is independently H or C₁-C₃ alkyl;

j1 is 1, 2, or 3;

k1 is 1, 2, or 3; and

Q₂ is absent, C(O), NHC(O)CH₂, or O(CH₂)₁₋₂;

wherein the Linker is covalently bonded to a Degron via the

next to Q₂, and covalently bonded to a Targeting Ligand via the

next to Z₂.

For a Linker of Formula L2:

-   (1) In one embodiment, p4 is an integer selected from 0 to 10-   (2) In one embodiment, p4 is an integer selected from 1 to 10.-   (3) In one embodiment, p4 is selected from 1, 2, 3, 4, 5, and 6.-   (4) In one embodiment, p4 is 0, 1, 3, or 5.-   (5) In one embodiment, p4 is 0, 1, 2, or 3.-   (6) In one embodiment, p4 is 0.-   (7) In one embodiment, p4 is 1.-   (8) In one embodiment, p4 is 2.-   (9) In one embodiment, p4 is 3.-   (10) In one embodiment, p4 is 4.-   (11) In one embodiment, p4 is 5.-   (12) In one embodiment, p4′ is an integer selected from 0 to 10.-   (13) In one embodiment, p4′ is an integer selected from 1 to 10.-   (14) In one embodiment, p4′ is selected from 1, 2, 3, 4, 5, and 6.-   (15) In one embodiment, p4′ is 0, 1, 3, or 5.-   (16) In one embodiment, p4′ is 0, 1, 2, or 3.-   (17) In one embodiment, p4′ is 0.-   (18) In one embodiment, p4′ is 1.-   (19) In one embodiment, p4′ is 2.-   (20) In one embodiment, p4′ is 3.-   (21) In one embodiment, p4′ is 4.-   (22) In one embodiment, p4′ is 5.-   (23) In one embodiment, p5 is an integer selected from 0 to 10.-   (24) In one embodiment, p5 is selected from 0, 1, 2, 3, 4, 5, and 6.-   (25) In one embodiment, p5 is 0, 1, 2, or 3.-   (26) In one embodiment, p5 is 0.-   (27) In one embodiment, p5 is 1.-   (28) In one embodiment, p5 is 2.-   (29) In one embodiment, p5 is 3.-   (30) In one embodiment, p6 is an integer selected from 1 to 5.-   (31) In one embodiment, p6 is 2, 3, 4, or 5.-   (32) In one embodiment, p6 is 0, 1, 2, or 3.-   (33) In one embodiment, p6 is 0.-   (34) In one embodiment, p6 is 1.-   (35) In one embodiment, p6 is 2.-   (36) In one embodiment, p6 is 3.-   (37) In one embodiment, p6 is 4.-   (38) In one embodiment, at least one W₁ is CH₂.-   (39) In one embodiment, at least one W₁ is O.-   (40) In one embodiment, at least one W₁ is S.-   (41) In one embodiment, at least one W₁ is NH.-   (42) In one embodiment, at least one W₁ is NR₂₅; and each R₂₅ is    independently C₁-C₃ alkyl selected from methyl, ethyl, and propyl.-   (43) In one embodiment, each W₁ is O.-   (44) In one embodiment, each W₁ is CH₂.-   (45) In one embodiment, W₂ is NR₂₅C(O)CH₂—; and R₂₅ is C₁-C₃ alkyl    selected from methyl, ethyl, and propyl.-   (46) In one embodiment, W₂ is NR₂₅C(O)CH₂; and R₂₅ is H.-   (47) In one embodiment, W₂ is

-   (48) In one embodiment, W₂ is

-   (49) In one embodiment, W₂ is

-   (50) In one embodiment, at least one W₃ is CH₂.-   (51) In one embodiment, at least one W₃ is O.-   (52) In one embodiment, at least one W₃ is S.-   (53) In one embodiment, at least one W₃ is NH.-   (54) In one embodiment, at least one W₃ is NR₂₅; and each R₂₅ is    independently C₁-C₃ alkyl selected from methyl, ethyl, and propyl.-   (55) In one embodiment, each W₃ is O.-   (56) In one embodiment, each W₃ is CH₂.-   (57) In one embodiment, j1 is 1, 2, or 3.-   (58) In one embodiment, j is 1.-   (59) In one embodiment, j is 2.-   (60) In one embodiment, j is 3.-   (61) In one embodiment, j1l is 2 or 3.-   (62) In one embodiment, j1 is 1 or 2.-   (63) In one embodiment, k1 is 1, 2, or 3.-   (64) In one embodiment, k1 is 1.-   (65) In one embodiment, k1 is 2.-   (66) In one embodiment, k1 is 3.-   (67) In one embodiment, k1 is 2 or 3.-   (68) In one embodiment, k1 is 1 or 2.-   (69) In one embodiment, Q₂ is absent.-   (70) In one embodiment, Q₂ is NHC(O)CH₂.-   (71) In one embodiment, Q₂ is O(CH₂)₁₋₂.-   (72) In one embodiment, Q₂ is OCH₂.-   (73) In one embodiment, Q₂ is OCH₂CH₂.-   (74) In one embodiment, Q₂ is OCH₂C(O).-   (75) In one embodiment, Q₂ is C(O).-   (76) In one embodiment, Z₂ is absent.-   (77) In one embodiment, Z₂ is O(CH₂)_(j1)C(O)NR₂₅; and R₂₅ is C₁-C₃    alkyl selected from methyl, ethyl, and propyl.-   (78) In one embodiment, Z₂ is O(CH₂)_(j1)C(O)NR₂₅; and R₂₅ is H.-   (79) In one embodiment, Z₂ is O(CH₂)_(j1)C(O)NR₂₅; R₂₅ is C₁-C₃    alkyl selected from methyl, ethyl, and propyl; and j1 is 1.-   (80) In one embodiment, Z₂ is O(CH₂)_(j1)C(O)NR₂₅; R₂₅ is H; and j1    is 1.-   (81) In one embodiment, Z₂ is O(CH₂)_(j1)C(O)NR₂₅; R₂₅ is C₁-C₃    alkyl selected from methyl, ethyl, and propyl; and j1 is 2.-   (82) In one embodiment, Z₂ is O(CH₂)_(j1)C(O)NR₂₅; R₂₅ is H; and j1    is 2.-   (83) In one embodiment, Z₂ is O(CH₂)_(j1)C(O)NR₂₅; R₂₅ is C₁-C₃    alkyl selected from methyl, ethyl, and propyl; and j1 is 3.-   (84) In one embodiment, Z₂ is O(CH₂)_(j1)C(O)NR₂₅; and R₂₅ is H; and    j1 is 3.-   (85) In one embodiment, Z₂ is C(O)NR₂₅; and R₂₅ is H.-   (86) In one embodiment, Z₂ is C(O)NR₂₅; and R₂₅ is C₁-C₃ alkyl    selected from methyl, ethyl, and propyl.-   (87) In one embodiment, Z₂ is (CH₂)_(j1)C(O)NR₂₅; and R₂₅ is H.-   (88) In one embodiment, Z₂ is (CH₂)_(j1)C(O)NR₂₅; and R₂₅ is C₁-C₃    alkyl selected from methyl, ethyl, and propyl.-   (89) In one embodiment, Z₂ is (CH₂)_(j1)C(O)NR₂₅; R₂₅ is H; and j1    is 1.-   (90) In one embodiment, Z₂ is (CH₂)_(j1)C(O)NR₂₅; R₂₅ is C₁-C₃ alkyl    selected from methyl, ethyl, and propyl; and j1 is 1-   (91) In one embodiment, Z₂ is (CH₂)_(j1)C(O)NR₂₅; R₂₅ is H; and j1    is 2.-   (92) In one embodiment, Z₂ is (CH₂)_(j1)C(O)NR₂₅; R₂₅ is C₁-C₃ alkyl    selected from methyl, ethyl, and propyl; and j1 is 2.-   (93) In one embodiment, Z₂ is (CH₂)_(j1)C(O)NR₂₅; R₂₅ is H; and j1    is 3.-   (94) In one embodiment, Z₂ is (CH₂)_(j1)C(O)NR₂₅; R₂₅ is C₁-C₃ alkyl    selected from methyl, ethyl, and propyl; and j1 is 3.-   (95) In one embodiment, Z₂ is NR₂₅C(O); and R₂₅ is H.-   (96) In one embodiment, Z₂ is NR₂₅C(O); and R₂₅ is C₁-C₃ alkyl    selected from methyl, ethyl, and propyl.-   (97) In one embodiment, Z₂ is (CH₂)_(j1)NR₂₅C(O); and R₂₅ is H.-   (98) In one embodiment, Z₂ is (CH₂)_(j1)NR₂₅C(O); and R₂₅ is C₁-C₃    alkyl selected from methyl, ethyl, and propyl.-   (99) In one embodiment, Z₂ is (CH₂)_(j1)NR₂₅C(O); R₂₅ is H; and j1    is 1.-   (100) In one embodiment, Z₂ is (CH₂)_(j1)NR₂₅C(O); R₂₅ is C₁-C₃    alkyl selected from methyl, ethyl, and propyl; and j1 is 1-   (101) In one embodiment, Z₂ is (CH₂)_(j1)NR₂₅C(O); R₂₅ is H; and j1    is 2.-   (102) In one embodiment, Z₂ is (CH₂)_(j1)NR₂₅C(O); R₂₅ is C₁-C₃    alkyl selected from methyl, ethyl, and propyl; and j1 is 2.-   (103) In one embodiment, Z₂ is (CH₂)_(j1)NR₂₅C(O); R₂₅ is H; and j1    is 3.-   (104) In one embodiment, Z₂ is (CH₂)_(j1)NR₂₅C(O); R₂₅ is C₁-C₃    alkyl selected from methyl, ethyl, and propyl; and j1 is 3.-   (105) In one embodiment, Z₂ is (CH₂)_(k1)NR₂₅(CH₂)_(j1)C(O)NR₂₅; and    each R₂₅ is independently H or C₁-C₃ alkyl selected from methyl,    ethyl, and propyl.-   (106) In one embodiment, Z₂ is (CH₂)_(k1)NR₂₅(CH₂)_(j1)C(O)NR₂₅; and    one of R₂₅ is H and one of R₂₅ is C₁-C₃ alkyl selected from methyl,    ethyl, and propyl. In one embodiment, Z₂ is    (CH₂)_(k1)NR₂₅(CH₂)_(j1)C(O)NH.-   (107) In one embodiment, Z₂ is (CH₂)_(k1)NR₂₅(CH₂)_(j1)C(O)NR₂₅;    each R₂₅ is independently H or C₁-C₃ alkyl selected from methyl,    ethyl, and propyl; and j1 is 1.-   (108) In one embodiment, Z₂ is (CH₂)_(k1)NR₂₅(CH₂)_(j1)C(O)NR₂₅;    each R₂₅ is independently H or C₁-C₃ alkyl selected from methyl,    ethyl, and propyl; and k1 is 1.-   (109) In one embodiment, Z₂ is (CH₂)_(k1)NR₂₅(CH₂)_(j1)C(O)NR₂₅;    each R₂₅ is independently H or C₁-C₃ alkyl selected from methyl,    ethyl, and propyl; j1 is 1; and k1 is 1.-   (110) In one embodiment, Z₂ is (CH₂)_(k1)NR₂₅(CH₂)_(j1)C(O)NR₂₅; one    of R₂₅ is H and one of R₂₅ is C₁-C₃ alkyl selected from methyl,    ethyl, and propyl; and j1 is 1. In one embodiment, Z₂ is    (CH₂)_(k1)NR₂₅(CH₂)C(O)NH.-   (111) In one embodiment, Z₂ is (CH₂)_(k1)NR₂₅(CH₂)_(j1)C(O)NR₂₅; one    of R₂₅ is H and one of R₂₅ is C₁-C₃ alkyl selected from methyl,    ethyl, and propyl; and k1 is 1. In one embodiment, Z₂ is    (CH₂)NR₂₅(CH₂)_(j1)C(O)NH.-   (112) In one embodiment, Z₂ is (CH₂)_(k1)NR₂₅(CH₂)_(j1)C(O)NR₂₅; one    of R₂₅ is H and one of R₂₅ is C₁-C₃ alkyl selected from methyl,    ethyl, and propyl; j1 is 1; and k1 is 1. In one embodiment, Z₂ is    (CH₂)NR₂₅(CH₂)C(O)NH. In one embodiment, Z₂ is    (CH₂)N(CH₃)(CH₂)C(O)NH.-   (113) In one embodiment, Z₂ is (CH₂)_(k1)NR₂₅(CH₂)_(j1)C(O)NR₂₅;    each R₂₅ is independently H or C₁-C₃ alkyl selected from methyl,    ethyl, and propyl; and j1 is 2.-   (114) In one embodiment, Z₂ is (CH₂)_(k1)NR₂₅(CH₂)_(j1)C(O)NR₂₅;    each R₂₅ is independently H or C₁-C₃ alkyl selected from methyl,    ethyl, and propyl; and k1 is 2.-   (115) In one embodiment, Z₂ is (CH₂)_(k1)NR₂₅(CH₂)_(j1)C(O)NR₂₅; one    of R₂₅ is H and one of R₂₅ is C₁-C₃ alkyl selected from methyl,    ethyl, and propyl; and j1 is 2. In one embodiment, Z₂ is    (CH₂)_(k1)NR₂₅(CH₂)₂C(O)NH.-   (116) In one embodiment, Z₂ is (CH₂)_(k1)NR₂₅(CH₂)_(j1)C(O)NR₂₅; one    of R₂₅ is H and one of R₂₅ is C₁-C₃ alkyl selected from methyl,    ethyl, and propyl; and k1 is 2. In one embodiment, Z₂ is    (CH₂)₂NR₂₅(CH₂)_(j1)C(O)NH.-   (117) In one embodiment, Z₂ is (CH₂)_(k1)NR₂₅(CH₂)_(j1)C(O)NR₂₅;    each R₂₅ is independently H or C₁-C₃ alkyl selected from methyl,    ethyl, and propyl; and j1 is 3.-   (118) In one embodiment, Z₂ is (CH₂)_(k1)NR₂₅(CH₂)_(j1)C(O)NR₂₅;    each R₂₅ is independently H or C₁-C₃ alkyl selected from methyl,    ethyl, and propyl; and k1 is 3.-   (119) In one embodiment, Z₂ is (CH₂)_(k1)NR₂₅(CH₂)_(j1)C(O)NR₂₅; one    of R₂₅ is H and one of R₂₅ is C₁-C₃ alkyl selected from methyl,    ethyl, and propyl; and j1 is 3. In one embodiment, Z₂ is    (CH₂)_(k1)NR₂₅(CH₂)₃C(O)NH.-   (120) In one embodiment, Z₂ is (CH₂)_(k1)NR₂₅(CH₂)_(j1)C(O)NR₂₅; one    of R₂₅ is H and one of R₂₅ is C₁-C₃ alkyl selected from methyl,    ethyl, and propyl; and k1 is 3. In one embodiment, Z₂ is    (CH₂)₃NR₂₅(CH₂)_(j1)C(O)NH.-   (121) In one embodiment, Z₂ is NR₂₅(CH₂)_(j1)C(O)NR₂₅; and each R₂₅    is independently H or C₁-C₃ alkyl selected from methyl, ethyl, and    propyl.-   (122) In one embodiment, Z₂ is NR₂₅(CH₂)_(j1)C(O)NR₂₅; and each R₂₅    is H.-   (123) In one embodiment, Z₂ is NR₂₅(CH₂)_(j1)C(O)NR₂₅; one of R₂₅ is    H and one of R₂₅ is C₁-C₃ alkyl selected from methyl, ethyl, and    propyl; and j1 is 1.-   (124) In one embodiment, Z₂ is NR₂₅(CH₂)_(j1)C(O)NR₂₅; R₂₅ is H; and    j1 is 1.-   (125) In one embodiment, Z₂ is NR₂₅(CH₂)_(j1)C(O)NR₂₅; one of R₂₅ is    H and one of R₂₅ is C₁-C₃ alkyl selected from methyl, ethyl, and    propyl; and j1 is 2.-   (126) In one embodiment, Z₂ is NR₂₅(CH₂)_(j1)C(O)NR₂₅; R₂₅ is H; and    j1 is 2.-   (127) In one embodiment, Z₂ is NR₂₅(CH₂)_(j1)C(O)NR₂₅; one of R₂₅ is    H and one of R₂₅ is C₁-C₃ alkyl selected from methyl, ethyl, and    propyl; and j1 is 3.-   (128) In one embodiment, Z₂ is absent and p6 is 1.-   (129) In one embodiment, Z₂ is absent and p6 is 2.-   (130) In one embodiment, Z₂ is absent and p6 is 3.-   (131) In one embodiment, Z₂ is absent, p6 is 1, and p4 is 1-5.-   (132) In one embodiment, Z₂ is absent, p6 is 1, and p4 is 1.-   (133) In one embodiment, Z₂ is absent, p6 is 1, and p4 is 2.-   (134) In one embodiment, Z₂ is absent, p6 is 1, and p4 is 3.-   (135) In one embodiment, Z₂ is absent, p6 is 1, and p4 is 4.-   (136) In one embodiment, Z₂ is absent, p6 is 1, and p4 is 5.-   (137) In one embodiment, Z₂ is absent, p6 is 2, and p4 is 1-5.-   (138) In one embodiment, Z₂ is absent, p6 is 2, and p4 is 1.-   (139) In one embodiment, Z₂ is absent, p6 is 2, and p4 is 2.-   (140) In one embodiment, Z₂ is absent, p6 is 2, and p4 is 3.-   (141) In one embodiment, Z₂ is absent, p6 is 2, and p4 is 4.-   (142) In one embodiment, Z₂ is absent, p6 is 2, and p4 is 5.-   (143) In one embodiment, Z₂ is absent, p6 is 2, and p4 is 1-5.-   (144) In one embodiment, Z₂ is absent, p6 is 2, and p4 is 1.-   (145) In one embodiment, Z₂ is absent, p6 is 2, and p4 is 2.-   (146) In one embodiment, Z₂ is absent, p6 is 2, and p4 is 3.-   (147) In one embodiment, Z₂ is absent, p6 is 2, and p4 is 4.-   (148) In one embodiment, Z₂ is absent, p6 is 2, and p4 is 5.-   (149) In one embodiment, Z₂ is absent, p6 is 1, p4 is 1, and p4′ is    1.-   (150) In one embodiment, Z₂ is absent, p6 is 1, p4 is 1, and p4′ is    2.-   (151) In one embodiment, Z₂ is absent, p6 is 1, p4 is 1, and p4′ is    3.-   (152) In one embodiment, Z₂ is absent, p6 is 1, p4 is 1, and p4′ is    4.-   (153) In one embodiment, Z₂ is absent, p6 is 1, p4 is 1, and p4′ is    5.-   (154) In one embodiment, Z₂ is absent, p6 is 1, p4 is 2, and p4′ is    1.-   (155) In one embodiment, Z₂ is absent, p6 is 1, p4 is 2, and p4′ is    2.-   (156) In one embodiment, Z₂ is absent, p6 is 1, p4 is 2, and p4′ is    3.-   (157) In one embodiment, Z₂ is absent, p6 is 1, p4 is 2, and p4′ is    4.-   (158) In one embodiment, Z₂ is absent, p6 is 1, p4 is 2, and p4′ is    5.-   (159) In one embodiment, Z₂ is absent, p6 is 1, p4 is 3, and p4′ is    1.-   (160) In one embodiment, Z₂ is absent, p6 is 1, p4 is 3, and p4′ is    2.-   (161) In one embodiment, Z₂ is absent, p6 is 1, p4 is 3, and p4′ is    3.-   (162) In one embodiment, Z₂ is absent, p6 is 1, p4 is 3, and p4′ is    4.-   (163) In one embodiment, Z₂ is absent, p6 is 1, p4 is 3, and p4′ is    5.-   (164) In one embodiment, Z₂ is absent, p6 is 1, p4 is 4, and p4′ is    1.-   (165) In one embodiment, Z₂ is absent, p6 is 1, p4 is 4, and p4′ is    2.-   (166) In one embodiment, Z₂ is absent, p6 is 1, p4 is 4, and p4′ is    3.-   (167) In one embodiment, Z₂ is absent, p6 is 1, p4 is 4, and p4′ is    4.-   (168) In one embodiment, Z₂ is absent, p6 is 1, p4 is 4, and p4′ is    5.-   (169) In one embodiment, Z₂ is absent, p6 is 1, p4 is 5, and p4′ is    1.-   (170) In one embodiment, Z₂ is absent, p6 is 1, p4 is 5, and p4′ is    2.-   (171) In one embodiment, Z₂ is absent, p6 is 1, p4 is 5, and p4′ is    3.-   (172) In one embodiment, Z₂ is absent, p6 is 1, p4 is 5, and p4′ is    4.-   (173) In one embodiment, Z₂ is absent, p6 is 1, p4 is 5, and p4′ is    5.-   (174) In one embodiment, Z₂ is absent, p6 is 2, p4 is 1, and p4′ is    1.-   (175) In one embodiment, Z₂ is absent, p6 is 2, p4 is 1, and p4′ is    2.-   (176) In one embodiment, Z₂ is absent, p6 is 2, p4 is 1, and p4′ is    3.-   (177) In one embodiment, Z₂ is absent, p6 is 2, p4 is 1, and p4′ is    4.-   (178) In one embodiment, Z₂ is absent, p6 is 2, p4 is 1, and p4′ is    5.-   (179) In one embodiment, Z₂ is absent, p6 is 2, p4 is 2, and p4′ is    1.-   (180) In one embodiment, Z₂ is absent, p6 is 2, p4 is 2, and p4′ is    2.-   (181) In one embodiment, Z₂ is absent, p6 is 2, p4 is 2, and p4′ is    3.-   (182) In one embodiment, Z₂ is absent, p6 is 2, p4 is 2, and p4′ is    4.-   (183) In one embodiment, Z₂ is absent, p6 is 2, p4 is 2, and p4′ is    5.-   (184) In one embodiment, Z₂ is absent, p6 is 2, p4 is 3, and p4′ is    1.-   (185) In one embodiment, Z₂ is absent, p6 is 2, p4 is 3, and p4′ is    2.-   (186) In one embodiment, Z₂ is absent, p6 is 2, p4 is 3, and p4′ is    3.-   (187) In one embodiment, Z₂ is absent, p6 is 2, p4 is 3, and p4′ is    4.-   (188) In one embodiment, Z₂ is absent, p6 is 2, p4 is 3, and p4′ is    5.-   (189) In one embodiment, Z₂ is absent, p6 is 2, p4 is 4, and p4′ is    1.-   (190) In one embodiment, Z₂ is absent, p6 is 2, p4 is 4, and p4′ is    2.-   (191) In one embodiment, Z₂ is absent, p6 is 2, p4 is 4, and p4′ is    3.-   (192) In one embodiment, Z₂ is absent, p6 is 2, p4 is 4, and p4′ is    4.-   (193) In one embodiment, Z₂ is absent, p6 is 2, p4 is 4, and p4′ is    5.-   (194) In one embodiment, Z₂ is absent, p6 is 2, p4 is 5, and p4′ is    1.-   (195) In one embodiment, Z₂ is absent, p6 is 2, p4 is 5, and p4′ is    2.-   (196) In one embodiment, Z₂ is absent, p6 is 2, p4 is 5, and p4′ is    3.-   (197) In one embodiment, Z₂ is absent, p6 is 2, p4 is 5, and p4′ is    4.-   (198) In one embodiment, Z₂ is absent, p6 is 2, p4 is 5, and p4′ is    5.-   (199) In one embodiment, Z₂ is absent, p6 is 1, and W₁ is O.-   (200) In one embodiment, Z₂ is absent, p6 is 2, and W₁ is O.-   (201) In one embodiment, Z₂ is absent, p6 is 3, and W₁ is O.-   (202)-   (203) In one embodiment, Z₂ is absent, p6 is 1, p4 is 1, p4′ is 1,    and W₁ is O.-   (204) In one embodiment, Z₂ is absent, p6 is 1, p4 is 1, p4′ is 2,    and W₁ is O.-   (205) In one embodiment, Z₂ is absent, p6 is 1, p4 is 1, p4′ is 3,    and W₁ is O.-   (206) In one embodiment, Z₂ is absent, p6 is 1, p4 is 1, p4′ is 4,    and W₁ is O.-   (207) In one embodiment, Z₂ is absent, p6 is 1, p4 is 1, p4′ is 5,    and W₁ is O.-   (208) In one embodiment, Z₂ is absent, p6 is 1, p4 is 2, p4′ is 1,    and W₁ is O.-   (209) In one embodiment, Z₂ is absent, p6 is 1, p4 is 2, p4′ is 2,    and W₁ is O.-   (210) In one embodiment, Z₂ is absent, p6 is 1, p4 is 2, p4′ is 3,    and W₁ is O.-   (211) In one embodiment, Z₂ is absent, p6 is 1, p4 is 2, p4′ is 4,    and W₁ is O.-   (212) In one embodiment, Z₂ is absent, p6 is 1, p4 is 2, p4′ is 5,    and W₁ is O.-   (213) In one embodiment, Z₂ is absent, p6 is 1, p4 is 3, p4′ is 1,    and W₁ is O.-   (214) In one embodiment, Z₂ is absent, p6 is 1, p4 is 3, p4′ is 2,    and W₁ is O.-   (215) In one embodiment, Z₂ is absent, p6 is 1, p4 is 3, p4′ is 3,    and W₁ is O.-   (216) In one embodiment, Z₂ is absent, p6 is 1, p4 is 3, p4′ is 4,    and W₁ is O.-   (217) In one embodiment, Z₂ is absent, p6 is 1, p4 is 3, p4′ is 5,    and W₁ is O.-   (218) In one embodiment, Z₂ is absent, p6 is 1, p4 is 4, p4′ is 1,    and W₁ is O.-   (219) In one embodiment, Z₂ is absent, p6 is 1, p4 is 4, p4′ is 2,    and W₁ is O.-   (220) In one embodiment, Z₂ is absent, p6 is 1, p4 is 4, p4′ is 3,    and W₁ is O.-   (221) In one embodiment, Z₂ is absent, p6 is 1, p4 is 4, p4′ is 4,    and W₁ is O.-   (222) In one embodiment, Z₂ is absent, p6 is 1, p4 is 4, p4′ is 5,    and W₁ is O.-   (223) In one embodiment, Z₂ is absent, p6 is 1, p4 is 5, p4′ is 1,    and W is O.-   (224) In one embodiment, Z₂ is absent, p6 is 1, p4 is 5, p4′ is 2,    and W is O.-   (225) In one embodiment, Z₂ is absent, p6 is 1, p4 is 5, p4′ is 3,    and W is O.-   (226) In one embodiment, Z₂ is absent, p6 is 1, p4 is 5, p4′ is 4,    and W is O.-   (227) In one embodiment, Z₂ is absent, p6 is 1, p4 is 5, p4′ is 5,    and W is O.-   (228) In one embodiment, Z₂ is absent, p6 is 1, p4 is 1, p4′ is 1,    and W₁ is CH₂.-   (229) In one embodiment, Z₂ is absent, p6 is 1, p4 is 1, p4′ is 2,    and W₁ is CH₂.-   (230) In one embodiment, Z₂ is absent, p6 is 1, p4 is 1, p4′ is 3,    and W₁ is CH₂.-   (231) In one embodiment, Z₂ is absent, p6 is 1, p4 is 1, p4′ is 4,    and W₁ is CH₂.-   (232) In one embodiment, Z₂ is absent, p6 is 1, p4 is 1, p4′ is 5,    and W₁ is CH₂.-   (233) In one embodiment, Z₂ is absent, p6 is 1, p4 is 2, p4′ is 1,    and W₁ is CH₂.-   (234) In one embodiment, Z₂ is absent, p6 is 1, p4 is 2, p4′ is 2,    and W₁ is CH₂.-   (235) In one embodiment, Z₂ is absent, p6 is 1, p4 is 2, p4′ is 3,    and W₁ is CH₂.-   (236) In one embodiment, Z₂ is absent, p6 is 1, p4 is 2, p4′ is 4,    and W₁ is CH₂.-   (237) In one embodiment, Z₂ is absent, p6 is 1, p4 is 2, p4′ is 5,    and W₁ is CH₂.-   (238) In one embodiment, Z₂ is absent, p6 is 1, p4 is 3, p4′ is 1,    and W₁ is CH₂.-   (239) In one embodiment, Z₂ is absent, p6 is 1, p4 is 3, p4′ is 2,    and W₁ is CH₂.-   (240) In one embodiment, Z₂ is absent, p6 is 1, p4 is 3, p4′ is 3,    and W₁ is CH₂.-   (241) In one embodiment, Z₂ is absent, p6 is 1, p4 is 3, p4′ is 4,    and W₁ is CH₂.-   (242) In one embodiment, Z₂ is absent, p6 is 1, p4 is 3, p4′ is 5,    and W₁ is CH₂.-   (243) In one embodiment, Z₂ is absent, p6 is 1, p4 is 4, p4′ is 1,    and W₁ is CH₂.-   (244) In one embodiment, Z₂ is absent, p6 is 1, p4 is 4, p4′ is 2,    and W₁ is CH₂.-   (245) In one embodiment, Z₂ is absent, p6 is 1, p4 is 4, p4′ is 3,    and W₁ is CH₂.-   (246) In one embodiment, Z₂ is absent, p6 is 1, p4 is 4, p4′ is 4,    and W₁ is CH₂.-   (247) In one embodiment, Z₂ is absent, p6 is 1, p4 is 4, p4′ is 5,    and W₁ is CH₂.-   (248) In one embodiment, Z₂ is absent, p6 is 1, p4 is 5, p4′ is 1,    and W is CH₂.-   (249) In one embodiment, Z₂ is absent, p6 is 1, p4 is 5, p4′ is 2,    and W is CH₂.-   (250) In one embodiment, Z₂ is absent, p6 is 1, p4 is 5, p4′ is 3,    and W is CH₂.-   (251) In one embodiment, Z₂ is absent, p6 is 1, p4 is 5, p4′ is 4,    and W is CH₂.-   (252) In one embodiment, Z₂ is absent, p6 is 1, p4 is 5, p4′ is 5,    and W is CH₂.-   (253) In one embodiment, Z₂ is absent, p6 is 2, p4 is 1, p4′ is 1,    and W₁ is O.-   (254) In one embodiment, Z₂ is absent, p6 is 2, p4 is 1, p4′ is 2,    and W₁ is O.-   (255) In one embodiment, Z₂ is absent, p6 is 2, p4 is 1, p4′ is 3,    and W₁ is O.-   (256) In one embodiment, Z₂ is absent, p6 is 2, p4 is 1, p4′ is 4,    and W₁ is O.-   (257) In one embodiment, Z₂ is absent, p6 is 2, p4 is 1, p4′ is 5,    and W₁ is O.-   (258) In one embodiment, Z₂ is absent, p6 is 2, p4 is 2, p4′ is 1,    and W₁ is O.-   (259) In one embodiment, Z₂ is absent, p6 is 2, p4 is 2, p4′ is 2,    and W₁ is O.-   (260) In one embodiment, Z₂ is absent, p6 is 2, p4 is 2, p4′ is 3,    and W₁ is O.-   (261) In one embodiment, Z₂ is absent, p6 is 2, p4 is 2, p4′ is 4,    and W₁ is O.-   (262) In one embodiment, Z₂ is absent, p6 is 2, p4 is 2, p4′ is 5,    and W₁ is O.-   (263) In one embodiment, Z₂ is absent, p6 is 2, p4 is 3, p4′ is 1,    and W₁ is O.-   (264) In one embodiment, Z₂ is absent, p6 is 2, p4 is 3, p4′ is 2,    and W₁ is O.-   (265) In one embodiment, Z₂ is absent, p6 is 2, p4 is 3, p4′ is 3,    and W₁ is O.-   (266) In one embodiment, Z₂ is absent, p6 is 2, p4 is 3, p4′ is 4,    and W₁ is O.-   (267) In one embodiment, Z₂ is absent, p6 is 2, p4 is 3, p4′ is 5,    and W₁ is O.-   (268) In one embodiment, Z₂ is absent, p6 is 2, p4 is 4, p4′ is 1,    and W₁ is O.-   (269) In one embodiment, Z₂ is absent, p6 is 2, p4 is 4, p4′ is 2,    and W₁ is O.-   (270) In one embodiment, Z₂ is absent, p6 is 2, p4 is 4, p4′ is 3,    and W₁ is O.-   (271) In one embodiment, Z₂ is absent, p6 is 2, p4 is 4, p4′ is 4,    and W₁ is O.-   (272) In one embodiment, Z₂ is absent, p6 is 2, p4 is 4, p4′ is 5,    and W₁ is O.-   (273) In one embodiment, Z₂ is absent, p6 is 2, p4 is 5, p4′ is 1,    and W is O.-   (274) In one embodiment, Z₂ is absent, p6 is 2, p4 is 5, p4′ is 2,    and W is O.-   (275) In one embodiment, Z₂ is absent, p6 is 2, p4 is 5, p4′ is 3,    and W is O.-   (276) In one embodiment, Z₂ is absent, p6 is 2, p4 is 5, p4′ is 4,    and W is O.-   (277) In one embodiment, Z₂ is absent, p6 is 2, p4 is 5, p4′ is 5,    and W is O.-   (278) In one embodiment, Z₂ is absent, p6 is 2, p4 is 1, p4′ is 1,    and W₁ is CH₂.-   (279) In one embodiment, Z₂ is absent, p6 is 2, p4 is 1, p4′ is 2,    and W₁ is CH₂.-   (280) In one embodiment, Z₂ is absent, p6 is 2, p4 is 1, p4′ is 3,    and W₁ is CH₂.-   (281) In one embodiment, Z₂ is absent, p6 is 2, p4 is 1, p4′ is 4,    and W₁ is CH₂.-   (282) In one embodiment, Z₂ is absent, p6 is 2, p4 is 1, p4′ is 5,    and W₁ is CH₂.-   (283) In one embodiment, Z₂ is absent, p6 is 2, p4 is 2, p4′ is 1,    and W₁ is CH₂.-   (284) In one embodiment, Z₂ is absent, p6 is 2, p4 is 2, p4′ is 2,    and W₁ is CH₂.-   (285) In one embodiment, Z₂ is absent, p6 is 2, p4 is 2, p4′ is 3,    and W₁ is CH₂.-   (286) In one embodiment, Z₂ is absent, p6 is 2, p4 is 2, p4′ is 4,    and W₁ is CH₂.-   (287) In one embodiment, Z₂ is absent, p6 is 2, p4 is 2, p4′ is 5,    and W₁ is CH₂.-   (288) In one embodiment, Z₂ is absent, p6 is 2, p4 is 3, p4′ is 1,    and W₁ is CH₂.-   (289) In one embodiment, Z₂ is absent, p6 is 2, p4 is 3, p4′ is 2,    and W₁ is CH₂.-   (290) In one embodiment, Z₂ is absent, p6 is 2, p4 is 3, p4′ is 3,    and W₁ is CH₂.-   (291) In one embodiment, Z₂ is absent, p6 is 2, p4 is 3, p4′ is 4,    and W₁ is CH₂.-   (292) In one embodiment, Z₂ is absent, p6 is 2, p4 is 3, p4′ is 5,    and W₁ is CH₂.-   (293) In one embodiment, Z₂ is absent, p6 is 2, p4 is 4, p4′ is 1,    and W₁ is CH₂.-   (294) In one embodiment, Z₂ is absent, p6 is 2, p4 is 4, p4′ is 2,    and W₁ is CH₂.-   (295) In one embodiment, Z₂ is absent, p6 is 2, p4 is 4, p4′ is 3,    and W₁ is CH₂.-   (296) In one embodiment, Z₂ is absent, p6 is 2, p4 is 4, p4′ is 4,    and W₁ is CH₂.-   (297) In one embodiment, Z₂ is absent, p6 is 2, p4 is 4, p4′ is 5,    and W₁ is CH₂.-   (298) In one embodiment, Z₂ is absent, p6 is 2, p4 is 5, p4′ is 1,    and W is CH₂.-   (299) In one embodiment, Z₂ is absent, p6 is 2, p4 is 5, p4′ is 2,    and W₁ is CH₂.-   (300) In one embodiment, Z₂ is absent, p6 is 2, p4 is 5, p4′ is 3,    and W₁ is CH₂.-   (301) In one embodiment, Z₂ is absent, p6 is 2, p4 is 5, p4′ is 4,    and W₁ is CH₂.-   (302) In one embodiment, Z₂ is absent, p6 is 2, p4 is 5, p4′ is 5,    and W₁ is CH₂.-   (303) In one embodiment, p4, p4′, Z₂, p6, W₁, W₂, and W₃ are each as    defined, where applicable, in any one of (1)-(302), and p5 is 0.-   (304) In one embodiment, p4, p4′, Z₂, p6, W₁, W₂, and W₃ are each as    defined, where applicable, in any one of (1)-(302), and p5 is 1.-   (305) In one embodiment, p4, p4′, Z₂, p6, W₁, W₂, and W₃ are each as    defined, where applicable, in any one of (1)-(302), and p5 is 2.-   (306) In one embodiment, p4, p4′, Z₂, p6, p5, W₁, and W₃ are each as    defined, where applicable, in any one of (1)-(44) and (50)-(305),    and W₂ is O.-   (307) In one embodiment, p4, p4′, Z₂, p6, p5, W₁, and W₃ are each as    defined, where applicable, in any one of (1)-(44) and (50)-(305),    and W₂ is CH₂.-   (308) In one embodiment, p4, p4′, Z₂, p6, p5, W₁, and W₂ are each as    defined, where applicable, in any one of (1)-(49) and (57)-(307),    and W₃ is NR₂₅C(O)CH₂.-   (309) In one embodiment, p4, p4′, Z₂, p6, p5, W₁, and W₂ are each as    defined, where applicable, in any one of (1)-(49) and (57)-(307),    and W₃ is NHC(O)CH₂.-   (310) In one embodiment, p4, p4′, Z₂, p6, p5, W₁, and W₂ are each as    defined, where applicable, in any one of (1)-(49) and (57)-(307),    and W₃ is

-   (311) In one embodiment, p4, p4′, Z₂, p6, p5, W₁, and W₂ are each as    defined, where applicable, in any one of (1)-(49) and (57)-(307),    and W₃ is

-   (312) In one embodiment, p4, p4′, Z₂, p6, p5, and W₁ are each as    defined, where applicable, in any one of (1)-(311), and Q₂ is    absent.-   (313) In one embodiment, p4, p4′, Z₂, p6, p5, W₁, W₂, and W₃ are    each as defined, where applicable, in any one of (1)-(311), and Q₂    is NHC(O)CH₂.-   (314) In one embodiment, p4, p4′, Z₂, p6, p5, W₁, W₂, and W₃ are    each as defined, where applicable, in any one of (1)-(311), and Q₂    is O(CH₂)₁₋₂.-   (315) In one embodiment, p4, p4′, Z₂, p6, p5, W₁, W₂, and W₃ are    each as defined, where applicable, in any one of (1)-(311), and Q₂    is O(CH₂).-   (316) In one embodiment, p4, p4′, Z₂, p6, p5, W₁, W₂, and W₃ are    each as defined, where applicable, in any one of (1)-(311), and Q₂    is O(CH₂CH₂).-   (317) In one embodiment, p4, p4′, Z₂, p6, p5, W₁, W₂, and W₃ are    each as defined, where applicable, in any one of (1)-(311), and Q₂    is C(O).-   (318) In one embodiment, p4, p4′, Z₂, p6, p5, W₁, W₂, and W₃ are    each as defined, where applicable, in any one of (1)-(311), and Q₂    is OCH₂C(O).

In one embodiment, the Linker-Targeting Ligand (TL) has the structureselected from Table M:

TABLE M

(L2a)

(L2b)

(L2c)

(L2d)

(L2e)

(L2f)

(L2g)

(L2h)

(L2i)

(L2j)

(L2k)

(L2l)

(L2m)

(L2n)

(L2o)

(L2p)

(L2q)

(L2r)

(L2s)

(L2t)

(L2u)

(L2v)

(L2w)

(L2x)wherein Z₂, W₁, W₃, Q₂, TL, R₂₅, p4, p4′, and p6 are each as describedabove.

Any one of the Degrons described herein can be covalently bound to anyone of the Linkers described herein. Any one of the Targeting Ligandsdescribed herein can be covalently bound to any one of the Linkersdescribed herein.

In one embodiment, the present application relates to the Degron-Linker(DL), wherein the Degron is of Formula D1, and the Linker is selectedfrom L2a-L2x. In one embodiment, the present application relates to theDegron-Linker (DL), wherein the Degron is of Formula D1, and the Linkeris selected from L2a-L2c. In one embodiment, the present applicationrelates to the Degron-Linker (DL), wherein the Degron is of Formula D1,and the Linker is selected from L2d-L2g. In one embodiment, the presentapplication relates to the Degron-Linker (DL), wherein the Degron is ofFormula D1, and the Linker is selected from L2h-L2k. In one embodiment,the present application relates to the Degron-Linker (DL), wherein theDegron is of Formula D1, and the Linker is selected from L2l-L2m. In oneembodiment, the present application relates to the Degron-Linker (DL),wherein the Degron is of Formula D1, and the Linker is selected fromL2n-L2p. In one embodiment, the present application relates to theDegron-Linker (DL), wherein the Degron is of Formula D1, and the Linkeris selected from L2q-L2t. In one embodiment, the present applicationrelates to the Degron-Linker (DL), wherein the Degron is of Formula D1,and the Linker is selected from L2u-L2x.

In one embodiment, the present application relates to the Degron-Linker(DL), wherein the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f,D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is selected fromL2a-L2x. In one embodiment, the present application relates to theDegron-Linker (DL), wherein the Degron is of Formula D1a, D1b, D1c, D1d,D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is selectedfrom L2a-L2c. In one embodiment, the present application relates to theDegron-Linker (DL), wherein the Degron is of Formula D1a, D1b, D1c, D1d,D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is selectedfrom L2d-L2g. In one embodiment, the present application relates to theDegron-Linker (DL), wherein the Degron is of Formula D1a, D1b, D1c, D1d,D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is selectedfrom L2h-L2k. In one embodiment, the present application relates to theDegron-Linker (DL), wherein the Degron is of Formula D1a, D1b, D1c, D1d,D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is selectedfrom L2l-L2m. In one embodiment, the present application relates to theDegron-Linker (DL), wherein the Degron is of Formula D1a, D1b, D1c, D1d,D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is selectedfrom L2n-L2p. In one embodiment, the present application relates to theDegron-Linker (DL), wherein the Degron is of Formula D1a, D1b, D1c, D1d,D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is selectedfrom L2q-L2t. In one embodiment, the present application relates to theDegron-Linker (DL), wherein the Degron is of Formula D1a, D1b, D1c, D1d,D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is selectedfrom L2u-L2x.

In one embodiment, the present application relates to the Degron-Linker(DL), wherein the Degron is of Formula D2, and the Linker is selectedfrom L2a-L2x. In one embodiment, the present application relates to theDegron-Linker (DL), wherein the Degron is of Formula D2, and the Linkeris selected from L2a-L2c. In one embodiment, the present applicationrelates to the Degron-Linker (DL), wherein the Degron is of Formula D2,and the Linker is selected from L2d-L2g. In one embodiment, the presentapplication relates to the Degron-Linker (DL), wherein the Degron is ofFormula D2, and the Linker is selected from L2h-L2k. In one embodiment,the present application relates to the Degron-Linker (DL), wherein theDegron is of Formula D2, and the Linker is selected from L2l-L2m. In oneembodiment, the present application relates to the Degron-Linker (DL),wherein the Degron is of Formula D2, and the Linker is selected fromL2n-L2p. In one embodiment, the present application relates to theDegron-Linker (DL), wherein the Degron is of Formula D2, and the Linkeris selected from L2q-L2t. In one embodiment, the present applicationrelates to the Degron-Linker (DL), wherein the Degron is of Formula D2,and the Linker is selected from L2u-L2x.

In one embodiment, the present application relates to the Degron-Linker(DL), wherein the Degron is of Formula D2a or D2b, and the Linker isselected from L2a-L2x. In one embodiment, the present applicationrelates to the Degron-Linker (DL), wherein the Degron is of Formula D2aor D2b, and the Linker is selected from L2a-L2c. In one embodiment, thepresent application relates to the Degron-Linker (DL), wherein theDegron is of Formula D2a or D2b, and the Linker is selected fromL2d-L2g. In one embodiment, the present application relates to theDegron-Linker (DL), wherein the Degron is of Formula D2a or D2b, and theLinker is selected from L2h-L2k. In one embodiment, the presentapplication relates to the Degron-Linker (DL), wherein the Degron is ofFormula D2a or D2b, and the Linker is selected from L2l-L2m. In oneembodiment, the present application relates to the Degron-Linker (DL),wherein the Degron is of Formula D2a or D2b, and the Linker is selectedfrom L2n-L2p. In one embodiment, the present application relates to theDegron-Linker (DL), wherein the Degron is of Formula D2a or D2b, and theLinker is selected from L2q-L2t. In one embodiment, the presentapplication relates to the Degron-Linker (DL), wherein the Degron is ofFormula D2a or D2b, and the Linker is selected from L2u-L2x.

In one embodiment, the present application relates to the Degron-Linker(DL), wherein the Degron is of Formula D2c or D2d, and the Linker isselected from L2a-L2x. In one embodiment, the present applicationrelates to the Degron-Linker (DL), wherein the Degron is of Formula D2cor D2d, and the Linker is selected from L2a-L2c. In one embodiment, thepresent application relates to the Degron-Linker (DL), wherein theDegron is of Formula D2c or D2d, and the Linker is selected fromL2d-L2g. In one embodiment, the present application relates to theDegron-Linker (DL), wherein the Degron is of Formula D2c or D2d, and theLinker is selected from L2h-L2k. In one embodiment, the presentapplication relates to the Degron-Linker (DL), wherein the Degron is ofFormula D2c or D2d, and the Linker is selected from L2l-L2m.

In one embodiment, the present application relates to the Degron-Linker(DL), wherein the Degron is of Formula D2c or D2d, and the Linker isselected from L2n-L2p. In one embodiment, the present applicationrelates to the Degron-Linker (DL), wherein the Degron is of Formula D2cor D2d, and the Linker is selected from L2q-L2t. In one embodiment, thepresent application relates to the Degron-Linker (DL), wherein theDegron is of Formula D2c or D2d, and the Linker is selected fromL2u-L2x.

In one embodiment, the Linker is designed and optimized based on SAR(structure-activity relationship) and X-ray crystallography of theTargeting Ligand with regard to the location of attachment for theLinker.

In one embodiment, the optimal Linker length and composition vary by theTargeting Ligand and can be estimated based upon X-ray structure of theTargeting Ligand bound to its target. Linker length and composition canbe also modified to modulate metabolic stability and pharmacokinetic(PK) and pharmacodynamics (PD) parameters.

Some embodiments of present application relate to the bifunctionalcompounds having one of the following structures in Table A:

TABLE A Structure

  Y = O, NH

  Y = O, NH

  Y = O, NH

  Y = O, NH

  Y = O, NH

  Y = O, NH

  Y = O, NH

  Y = O, NH

  Z₃ = CH₂, C═O Y = O, NH R = H, Me, Et

  R = H, Me, Et Y = O, NH Z₃ = CH₂, C═O

  Z₃ = CH₂, C═O Y = O, NH

  Y = O, NH Z₃ = CH₂, C═O

  Z₃ = CH₂, C═O Y = O, NH

  Z₃ = CH₂, C═O Y = O, NH

  Y = O, NH Z₃ = CH₂, C═O

  Z₃ = CH₂, C═O Y = O, NH

  Z₃ = CH₂, C═O Y = O, NH

  Y = O, NH Z₃ = CH₂, C═O

  Z₃ = CH₂, C═O Y = O, NH

  Y = O, NH Z₃ = CH₂, C═O

  R = H, Me, Et Y = O, NH Z₃ = CH₂, C═O

  R = H, Me, Et Z₃ = CH₂, C═O Y = O, NH

  Z₃ = CH₂, C═O Y = O, NH

  Z₃ = CH₂, C═O Y = O, NH

  R = H, CN Y = O, NH Z₃ = CH₂, C═O

  R = H, CN Y = O, NH Z₃ = CH₂, C═O

Some embodiments of present application relate to the bifunctionalcompounds having one of the following structures in Table C:

TABLE C Cmpd No. Structure I-1

I-2

I-3

I-4

I-5

Some of the foregoing compounds can comprise one or more asymmetriccenters, and thus can exist in various isomeric forms, e.g.,stereoisomers and/or diastereomers. Accordingly, compounds of theapplication may be in the form of an individual enantiomer, diastereomeror geometric isomer, or may be in the form of a mixture ofstereoisomers. In one embodiment, the compounds of the application areenantiopure compounds. In another embodiment, mixtures of stereoisomersor diastereomers are provided.

Furthermore, certain compounds, as described herein, may have one ormore double bonds that can exist as either the Z or E isomer, unlessotherwise indicated. The application additionally encompasses thecompounds as individual Z/E isomers substantially free of other E/Zisomers and alternatively, as mixtures of various isomers.

In one embodiment, the present application relates to compounds thattarget proteins, such as BTK for degradation, which have numerousadvantages over inhibitors of protein function (e.g., protein activity)and can a) overcome resistance in certain cases; b) prolong the kineticsof drug effect by destroying the protein, thus requiring resynthesis ofthe protein even after the compound has been metabolized; c) target allfunctions of a protein at once rather than a specific catalytic activityor binding event; d) expand the number of drug targets by including allproteins that a ligand can be developed for, rather than proteins whoseactivity (e.g., protein activity) can be affected by a small moleculeinhibitor, antagonist or agonist; and e) have increased potency comparedto inhibitors due to the possibility of the small molecule actingcatalytically.

Some embodiments of the present application relate to degradation orloss of 30% to 100% of the target protein. Some embodiments relate tothe loss of 50-100% of the target protein. Other embodiments relate tothe loss of 75-95% of the targeted protein.

A bifunctional compound of the present application (e.g., a bifunctionalcompound of any of the formulae described herein, or selected from anybifunctional compounds described herein) is capable of modulating (e.g.,decreasing) the amount of a targeted protein (e.g., BTK). A bifunctionalcompound of the present application (e.g., a bifunctional compound ofany of the formulae described herein, or selected from any bifunctionalcompounds described herein) is also capable of degrading a targetedprotein (e.g., BTK) through the UPP pathway. Accordingly, a bifunctionalcompound of the present application (e.g., a bifunctional compound ofany of the formulae described herein, or selected from any bifunctionalcompounds described herein) is capable of treating or preventing adisease or disorder in which BTK plays a role. A bifunctional compoundof the present application (e.g., a bifunctional compound of any of theformulae described herein, or selected from any bifunctional compoundsdescribed herein) is also capable of treating or preventing a disease ordisorder in which BTK plays a role or in which BTK is deregulated (e.g.,overexpressed).

Modulation of BTK through UPP-mediated degradation by a bifunctionalcompound of the application, such as those described herein, provides anovel approach to the treatment, prevention, or amelioration of diseasesor disorders in which BTK plays a role including, but not limited to,cancer and metastasis, inflammation, arthritis, systemic lupuserthematosus, skin-related disorders, pulmonary disorders,cardiovascular disease, ischemia, neurodegenerative disorders, liverdisease, gastrointestinal disorders, viral and bacterial infections,central nervous system disorders, Alzheimer's disease, Parkinson'sdisease, Huntington's disease, amyotrophic lateral sclerosis, spinalcord injury, and peripheral neuropathy. Further, modulation of BTKthrough UPP-mediated degradation by a bifunctional compound of theapplication, such as those described herein, also provides a newparadigm for treating, preventing, or ameliorating diseases or disordersin which BTK is deregulated.

In one embodiment, a bifunctional compound of the present application(e.g., a bifunctional compound of any of the formulae described herein,or selected from any bifunctional compounds described herein) is moreefficacious in treating a disease or condition (e.g., cancer) than, oris capable of treating a disease or condition resistant to, theTargeting Ligand, when the Targeting Ligand is administered alone (i.e.,not bonded to a Linker and a Degron). In one embodiment, a bifunctionalcompound of the present application (e.g., a bifunctional compound ofany of the formulae described herein, or selected from any bifunctionalcompounds described herein) is capable of modulating (e.g., decreasing)the amount of BTK, and thus is useful in treating a disease or condition(e.g., cancer) in which BTK plays a role.

In one embodiment, the bifunctional compound of the present applicationthat is more efficacious in treating a disease or condition than, or iscapable of treating a disease or condition resistant to, the TargetingLigand, when the Targeting Ligand is administered alone (i.e., notbonded to a Linker and a Degron), is more potent in inhibiting thegrowth of cells (e.g., cancer cells) or decreasing the viability ofcells (e.g., cancer cells), than the Targeting Ligand, when theTargeting Ligand is administered alone (i.e., not bonded to a Linker anda Degron). In one embodiment, the bifunctional compound inhibits thegrowth of cells (e.g., cancer cells) or decreases the viability of cells(e.g., cancer cells) at an IC₅₀ that is lower than the IC₅₀ of theTargeting Ligand (when the Targeting Ligand is administered alone (i.e.,not bonded to a Linker and a Degron)) for inhibiting the growth ordecreasing the viability of the cells. In one embodiment, the IC₅₀ ofthe bifunctional compound is at most 90%, 80%, 70%, 60%, 50%, 40%, 30%,20%, 10%, 8%, 5%, 4%, 3%, 2%, 1%, 0.8%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1%of the IC₅₀ of the Targeting Ligand. In one embodiment, the IC₅₀ of thebifunctional compound is at most 50%, 40%, 30%, 20%, 10%, 8%, 5%, 4%,3%, 2%, 1%, 0.8%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% of the IC₅₀ of theTargeting Ligand. In one embodiment, the IC₅₀ of the bifunctionalcompound is at most 30%, 20%, 10%, 8%, 5%, 4%, 3%, 2%, 1%, 0.8%, 0.5%,0.4%, 0.3%, 0.2%, or 0.1% of the IC₅₀ of the Targeting Ligand. In oneembodiment, the IC₅₀ of the bifunctional compound is at most 10%, 8%,5%, 4%, 3%, 2%, 1%, 0.8%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% of the IC₅₀ ofthe Targeting Ligand. In one embodiment, the IC₅₀ of the bifunctionalcompound is at most 5%, 4%, 3%, 2%, 1%, 0.8%, 0.5%, 0.4%, 0.3%, 0.2%, or0.1% of the IC₅₀ of the Targeting Ligand. In one embodiment, the IC₅₀ ofthe bifunctional compound is at most 2%, 1%, 0.8%, 0.5%, 0.4%, 0.3%,0.2%, or 0.1% of the IC₅₀ of the Targeting Ligand. In one embodiment,the IC₅₀ of the bifunctional compound is at most 1%, 0.8%, 0.5%, 0.4%,0.3%, 0.2%, or 0.1% of the IC₅₀ of the Targeting Ligand. In oneembodiment, the bifunctional compound inhibits the growth of cells(e.g., cancer cells) or decreases the viability of cells (e.g., cancercells) at an E_(max) that is lower than the E_(max) of the TargetingLigand (when the Targeting Ligand is administered alone (i.e., notbonded to a Linker and a Degron)) for inhibiting the growth ordecreasing the viability of the cells. In one embodiment, the E_(max) ofthe bifunctional compound is at most 90%, 80%, 70%, 60%, 50%, 40%, 30%,20%, 10%, 8%, 5%, 4%, 3%, 2%, or 1% of the E_(max) of the TargetingLigand. In one embodiment, the E_(max) of the bifunctional compound isat most 50%, 40%, 30%, 20%, 10%, 8%, 5%, 4%, 3%, 2%, or 1% of theE_(max) of the Targeting Ligand. In one embodiment, the E_(max) of thebifunctional compound is at most 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%,or 10% of the E_(max) of the Targeting Ligand.

In some embodiments, the inhibition of BTK activity is measured by IC₅₀.

In some embodiments, the inhibition of BTK activity is measured by EC₅₀.

Potency of the inhibitor can be determined by EC₅₀ value. A compoundwith a lower EC₅₀ value, as determined under substantially similarconditions, is a more potent inhibitor relative to a compound with ahigher EC₅₀ value. In some embodiments, the substantially similarconditions comprise determining a BTK-dependent cell proliferation, invitro or in vivo (e.g., in cells expressing BTK).

Potency of the inhibitor can also be determined by IC₅₀ value. Acompound with a lower IC₅o value, as determined under substantiallysimilar conditions, is a more potent inhibitor relative to a compoundwith a higher IC₅₀ value. In some embodiments, the substantially similarconditions comprise determining a BTK-dependent cell proliferation, invitro or in vivo (e.g., in cells expressing BTK).

In one embodiment, the bifunctional compounds of the present applicationare useful as anticancer agents, and thus may be useful in the treatmentof cancer, by effecting tumor cell death or inhibiting the growth oftumor cells. In certain exemplary embodiments, the disclosed anticanceragents are useful in the treatment of cancers and other proliferativedisorders, including, but not limited to breast cancer, cervical cancer,colon and rectal cancer, leukemia, lung cancer (e.g., non-small celllung cancer), melanoma, multiple myeloma, non-Hodgkin's lymphoma,ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer,leukemias (e.g., myeloid, lymphocytic, myelocytic and lymphoblasticleukemias), malignant melanomas, and T-cell lymphoma.

A “selective BTK inhibitor,” can be identified, for example, bycomparing the ability of a compound to inhibit BTK kinase activity toits ability to inhibit other kinases. For example, a substance may beassayed for its ability to inhibit BTK kinase activity, as well asanother kinase.

In some embodiments, the selectivity can be identified by measuring theEC₅₀ or IC₅₀ of the compounds.

Definitions

Listed below are definitions of various terms used in this application.These definitions apply to the terms as they are used throughout thisspecification and claims, unless otherwise limited in specificinstances, either individually or as part of a larger group.

The term “alkyl,” as used herein, refers to saturated, straight orbranched-chain hydrocarbon radicals containing, in certain embodiments,between one and six carbon atoms. For example C₁-C₃ alkyl includesmethyl, ethyl, n-propyl, and isopropyl. Examples of C₁-C₆ alkyl radicalsinclude, but are not limited to, methyl, ethyl, propyl, isopropyl,n-butyl, tert-butyl, neopentyl, and n-hexyl radicals.

The term “alkoxy” refers to an —O-alkyl radical. For example C₁-C₃alkoxy includes methoxy, ethoxy, n-propoxy, and isopropoxy. Examples ofC₁-C₆ alkyl radicals include, but are not limited to, methoxy, ethoxy,propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentoxy, and n-hexoxyradicals.

The terms “hal,” “halo,” and “halogen,” as used herein, refer to an atomselected from fluorine, chlorine, bromine and iodine.

The term “aryl,” as used herein, refers to a mono- or poly-cycliccarbocyclic ring system having one or more aromatic rings, fused ornon-fused, including, but not limited to, phenyl, naphthyl,tetrahydronaphthyl, indanyl, indenyl and the like.

The term “aralkyl,” as used herein, refers to an alkyl residue attachedto an aryl ring. Examples include, but are not limited to, benzyl,phenethyl and the like.

The term “cycloalkyl,” as used herein, denotes a monovalent groupderived from a monocyclic or polycyclic saturated or partiallyunsaturated carbocyclic ring compound. Examples of C₃-C₈ cycloalkylinclude, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyclopentyl and cyclooctyl; and examples ofC₃-C₁₂-cycloalkyl include, but not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2.2]octyl. Also contemplated is a monovalent group derived from a monocyclicor polycyclic carbocyclic ring compound having at least onecarbon-carbon double bond by the removal of a single hydrogen atom.Examples of such groups include, but are not limited to, cyclopropenyl,cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl,and the like.

The term “heteroaryl,” as used herein, refers to a mono- or poly-cyclic(e.g., bi-, or tri-cyclic or more) fused or non-fused, radical or ringsystem having at least one aromatic ring, having from five to ten ringatoms of which one ring atoms is selected from S, O, and N; zero, one,or two ring atoms are additional heteroatoms independently selected fromS, O, and N; and the remaining ring atoms are carbon. Heteroarylincludes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl,pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl,thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl,isoquinolinyl, benzimidazolyl, benzooxazolyl, quinoxalinyl, and thelike.

The term “heteroaralkyl,” as used herein, refers to an alkyl residueattached to a heteroaryl ring. Examples include, but are not limited to,pyridinylmethyl, pyrimidinylethyl and the like.

The term “heterocyclyl,” or “heterocycloalkyl,” as used herein, refersto a non-aromatic 3-, 4-, 5-, 6- or 7-membered ring or a bi- ortri-cyclic group fused of non-fused system, where (i) each ring containsbetween one and three heteroatoms independently selected from oxygen,sulfur and nitrogen, (ii) each 5-membered ring has 0 to 1 double bondsand each 6-membered ring has 0 to 2 double bonds, (iii) the nitrogen andsulfur heteroatoms may optionally be oxidized, and (iv) the nitrogenheteroatom may optionally be quaternized. Representativeheterocycloalkyl groups include, but are not limited to, [1,3]dioxolane,pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl,thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.

The term “alkylamino” refers to a group having the structure —NH(C₁-C₁₂alkyl), e.g., —NH(C₁-C₆ alkyl), where C₁-C₁₂ alkyl is as previouslydefined.

The term “dialkylamino” refers to a group having the structure —N(C₁-C₁₂alkyl)₂, e.g., —NH(C₁-C₆ alkyl), where C₁-C₁₂ alkyl is as previouslydefined.

The term “acyl” includes residues derived from acids, including but notlimited to carboxylic acids, carbamic acids, carbonic acids, sulfonicacids, and phosphorous acids. Examples include aliphatic carbonyls,aromatic carbonyls, aliphatic sulfonyls, aromatic sulfinyls, aliphaticsulfinyls, aromatic phosphates and aliphatic phosphates. Examples ofaliphatic carbonyls include, but are not limited to, acetyl, propionyl,2-fluoroacetyl, butyryl, 2-hydroxy acetyl, and the like.

In accordance with the application, any of the aryls, substituted aryls,heteroaryls and substituted heteroaryls described herein, can be anyaromatic group. Aromatic groups can be substituted or unsubstituted.

As described herein, compounds of the application may optionally besubstituted with one or more substituents, such as are illustratedgenerally above, or as exemplified by particular classes, subclasses,and species of the application. It will be appreciated that the phrase“optionally substituted” is used interchangeably with the phrase“substituted or unsubstituted.” In general, the term “substituted”,whether preceded by the term “optionally” or not, refers to thereplacement of hydrogen radicals in a given structure with the radicalof a specified substituent. Unless otherwise indicated, an optionallysubstituted group may have a substituent at each substitutable positionof the group, and when more than one position in any given structure maybe substituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. The terms “optionally substituted”, “optionally substitutedalkyl,” “optionally substituted “optionally substituted alkenyl,”“optionally substituted alkynyl”, “optionally substituted cycloalkyl,”“optionally substituted cycloalkenyl,” “optionally substituted aryl”,“optionally substituted heteroaryl,” “optionally substituted aralkyl”,“optionally substituted heteroaralkyl,” “optionally substitutedheterocycloalkyl,” and any other optionally substituted group as usedherein, refer to groups that are substituted or unsubstituted byindependent replacement of one, two, or three or more of the hydrogenatoms thereon with substituents including, but not limited to:

—F, —Cl, —Br, —I, —OH, protected hydroxy, —NO₂, —CN, —NH₂, protectedamino, —NH—C₁-C₁₂-alkyl, —NH—C₂-C₁₂-alkenyl, —NH—C₂-C₁₂-alkenyl,—NH—C₃-C₁₂-cycloalkyl, —NH-aryl, —NH-heteroaryl, —NH-heterocycloalkyl,-dialkylamino, -diarylamino, -diheteroarylamino, —O—C₁-C₁₂-alkyl,—O—C₂-C₁₂-alkenyl, —O—C₂-C₁₂-alkenyl, —O—C₃-C₁₂-cycloalkyl, —O-aryl,—O-heteroaryl, —O-heterocycloalkyl, —C(O)—C₁-C₁₂-alkyl,—C(O)—C₂-C₁₂-alkenyl, —C(O)—C₂-C₁₂-alkenyl, —C(O)—C₃-C₁₂-cycloalkyl,—C(O)-aryl, —C(O)-heteroaryl, —C(O)-heterocycloalkyl, —CONH₂,—CONH—C₁-C₁₂-alkyl, —CONH—C₂-C₁₂-alkenyl, —CONH—C₂-C₁₂-alkenyl,—CONH—C₃-C₁₂-cycloalkyl, —CONH-aryl, —CONH-heteroaryl,—CONH-heterocycloalkyl, —OCO₂—C₁-C₁₂-alkyl, —OCO₂—C₂-C₁₂-alkenyl,—OCO₂—C₂-C₁₂-alkenyl, —OCO₂—C₃-C₁₂-cycloalkyl, —OCO₂-aryl,—OCO₂-heteroaryl, —OCO₂-heterocycloalkyl, —OCONH₂, —OCONH—C₁-C₁₂-alkyl,—OCONH—C₂-C₁₂-alkenyl, —OCONH—C₂-C₁₂-alkenyl, —OCONH—C₃-C₁₂-cycloalkyl,—OCONH-aryl, —OCONH-heteroaryl, —OCONH-heterocycloalkyl,—NHC(O)—C₁-C₁₂-alkyl, —NHC(O)—C₂-C₁₂-alkenyl, —NHC(O)—C₂-C₁₂-alkenyl,—NHC(O)—C₃-C₁₂-cycloalkyl, —NHC(O)-aryl, —NHC(O)-heteroaryl,—NHC(O)-heterocycloalkyl, —NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₁₂-alkenyl,—NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂—C₃-C₁₂-cycloalkyl, —NHCO₂-aryl,—NHCO₂-heteroaryl, —NHCO₂-heterocycloalkyl, NHC(O)NH₂,—NHC(O)NH—C₁-C₁₂-alkyl, —NHC(O)NH—C₂-C₁₂-alkenyl,—NHC(O)NH—C₂-C₁₂-alkenyl, —NHC(O)NH—C₃-C₁₂-cycloalkyl, —NHC(O)NH-aryl,—NHC(O)NH-heteroaryl, NHC(O)NH-heterocycloalkyl, —NHC(S)NH₂,—NHC(S)NH—C₁-C₁₂-alkyl, —NHC(S)NH—C₂-C₁₂-alkenyl,—NHC(S)NH—C₂-C₁₂-alkenyl, —NHC(S)NH—C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂,—NHC(NH)NH—C₁-C₁₂-alkyl, —NHC(NH)NH—C₂-C₁₂-alkenyl,—NHC(NH)NH—C₂-C₁₂-alkenyl, —NHC(NH)NH—C₃-C₁₂-cycloalkyl,—NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NHheterocycloalkyl,—NHC(NH)—C₁-C₁₂-alkyl, —NHC(NH)—C₂-C₁₂-alkenyl, —NHC(NH)—C₂-C₁₂-alkenyl,—NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocycloalkyl, —C(NH)NH—C₁-C₁₂-alkyl,—C(NH)NH—C₂-C₁₂-alkenyl, —C(NH)NH—C₂-C₁₂-alkenyl,C(NH)NH—C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl,—C(NH)NHheterocycloalkyl, —S(O)—C₁-C₁₂-alkyl, —S(O)—C₂-C₁₂-alkenyl,—S(O)—C₂-C₁₂-alkenyl, —S(O)—C₃-C₁₂-cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl —SO₂NH₂, —SO₂NH—C₁-C₁₂-alkyl,—SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₃-C₁₂-cycloalkyl,—SO₂NH-aryl, —SO₂NH-heteroaryl, —SO₂NH-heterocycloalkyl,—NHSO₂—C₁-C₁₂-alkyl, —NHSO₂—C₂-C₁₂-alkenyl, —NHSO₂—C₂-C₁₂-alkenyl,—NHSO₂—C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C₃-C₁₂-cycloalkyl,polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, —SH,—S—C₁-C₁₂-alkyl, —S—C₂-C₁₂-alkenyl, —S—C₂-C₁₂-alkenyl,—S—C₃-C₁₂-cycloalkyl, —S-aryl, —S-heteroaryl, —S-heterocycloalkyl, ormethylthiomethyl.

It is understood that the aryls, heteroaryls, alkyls, and the like canbe substituted.

The term “cancer” includes, but is not limited to, the followingcancers: epidermoid Oral: buccal cavity, lip, tongue, mouth, pharynx;Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma,liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; Lung:bronchogenic carcinoma (squamous cell or epidermoid, undifferentiatedsmall cell, undifferentiated large cell, adenocarcinoma), alveolar(bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma,chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus(squamous cell carcinoma, larynx, adenocarcinoma, leiomyosarcoma,lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas(ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoidtumors, vipoma), small bowel or small intestines (adenocarcinoma,lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma,lipoma, neurofibroma, fibroma), large bowel or large intestines(adenocarcinoma, tubular adenoma, villous adenoma, hamartoma,leiomyoma), colon, colon-rectum, colorectal, rectum; Genitourinarytract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma,leukemia), bladder and urethra (squamous cell carcinoma, transitionalcell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma),testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma,choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma,fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma(hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma,angiosarcoma, hepatocellular adenoma, hemangioma, biliary passages;Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibroushistiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma(reticulum cell sarcoma), multiple myeloma, malignant giant cell tumorchordoma, osteochronfroma (osteocartilaginous exostoses), benignchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma andgiant cell tumors; Nervous system: skull (osteoma, hemangioma,granuloma, xanthoma, osteitis deformans), meninges (meningioma,meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma,glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform,oligodendroglioma, schwannoma, retinoblastoma, congenital tumors),spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological:uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumorcervical dysplasia), ovaries (ovarian carcinoma (serouscystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiedcarcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors,dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma),vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma(embryonal rhabdomyosarcoma), fallopian tubes (carcinoma), breast;Hematologic: blood (myeloid leukemia (acute and chronic), acutelymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferativediseases, multiple myeloma, myelodysplastic syndrome), Hodgkin'sdisease, non-Hodgkin's lymphoma (malignant lymphoma) hairy cell;lymphoid disorders; Skin: malignant melanoma, basal cell carcinoma,squamous cell carcinoma, Karposi's sarcoma, keratoacanthoma, molesdysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis,Thyroid gland: papillary thyroid carcinoma, follicular thyroidcarcinoma; medullary thyroid carcinoma, undifferentiated thyroid cancer,multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type2B, familial medullary thyroid cancer, pheochromocytoma, paraganglioma;and Adrenal glands: neuroblastoma. Thus, the term “cancerous cell” asprovided herein, includes a cell afflicted by any one of theabove-identified conditions.

The term “BTK” herein refers to Bruton's tyrosine kinase.

The term “subject” as used herein refers to a mammal. A subjecttherefore refers to, for example, dogs, cats, horses, cows, pigs, guineapigs, and the like. Preferably the subject is a human. When the subjectis a human, the subject may be referred to herein as a patient.

“Treat”, “treating” and “treatment” refer to a method of alleviating orabating a disease and/or its attendant symptoms.

As used herein, “preventing” or “prevent” describes reducing oreliminating the onset of the symptoms or complications of the disease,condition or disorder.

The term “targeted protein(s)” is used interchangeably with “targetprotein(s)”, unless the context clearly dictates otherwise. In oneembodiment, a “targeted protein” is BTK.

The terms “disease(s)”, “disorder(s)”, and “condition(s)” are usedinterchangeably, unless the context clearly dictates otherwise.

The term “therapeutically effective amount” of a bifunctional compoundor pharmaceutical composition of the application, as used herein, meansa sufficient amount of the bifunctional compound or pharmaceuticalcomposition so as to decrease the symptoms of a disorder in a subject.As is well understood in the medical arts a therapeutically effectiveamount of a bifunctional compound or pharmaceutical composition of thisapplication will be at a reasonable benefit/risk ratio applicable to anymedical treatment. It will be understood, however, that the total dailyusage of the compounds and compositions of the present application willbe decided by the attending physician within the scope of sound medicaljudgment. The specific inhibitory dose for any particular patient willdepend upon a variety of factors including the disorder being treatedand the severity of the disorder; the activity of the specific compoundemployed; the specific composition employed; the age, body weight,general health, sex and diet of the patient; the time of administration,route of administration, and rate of excretion of the specific compoundemployed; the duration of the treatment; drugs used in combination orcoincidental with the specific compound employed; and like factors wellknown in the medical arts.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts of the compounds formed by the process of the presentapplication which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge, etal. describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared insitu during the final isolation and purification of the compounds of theapplication, or separately by reacting the free base or acid functionwith a suitable acid or base.

Examples of pharmaceutically acceptable salts include, but are notlimited to, nontoxic acid addition salts: salts formed with inorganicacids such as hydrochloric acid, hydrobromic acid, phosphoric acid,sulfuric acid and perchloric acid, or with organic acids such as aceticacid, maleic acid, tartaric acid, citric acid, succinic acid or malonicacid. Other pharmaceutically acceptable salts include, but are notlimited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate,benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate,citrate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate,gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Representative alkali or alkaline earth metal salts includesodium, lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and arylsulfonate.

As used herein, the term “pharmaceutically acceptable ester” refers toesters of the bifunctional compounds formed by the process of thepresent application which hydrolyze in vivo and include those that breakdown readily in the human body to leave the parent compound or a saltthereof. Suitable ester groups include, for example, those derived frompharmaceutically acceptable aliphatic carboxylic acids, particularlyalkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which eachalkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.Examples of particular esters include, but are not limited to, formates,acetates, propionates, butyrates, acrylates and ethylsuccinates.

The term “pharmaceutically acceptable prodrugs” as used herein, refersto those prodrugs of the bifunctional compounds formed by the process ofthe present application which are, within the scope of sound medicaljudgment, suitable for use in contact with the tissues of humans andlower animals with undue toxicity, irritation, allergic response, andthe like, commensurate with a reasonable benefit/risk ratio, andeffective for their intended use, as well as the zwitterionic forms,where possible, of the compounds of the present application. “Prodrug”,as used herein, means a compound which is convertible in vivo bymetabolic means (e.g., by hydrolysis) to afford any compound delineatedby the formulae of the instant application. Various forms of prodrugsare known in the art, for example, as discussed in Bundgaard, (ed.),Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods inEnzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al.,(ed). “Design and Application of Prodrugs, Textbook of Drug Design andDevelopment, Chapter 5, 113-191 (1991); Bundgaard, et al., Journal ofDrug Deliver Reviews, 8:1-38(1992); Bundgaard, J. of PharmaceuticalSciences, 77:285 et seq. (1988); Higuchi and Stella (eds.) Prodrugs asNovel Drug Delivery Systems, American Chemical Society (1975); andBernard Testa & Joachim Mayer, “Hydrolysis In Drug And ProdrugMetabolism: Chemistry, Biochemistry And Enzymology,” John Wiley andSons, Ltd. (2002).

This application also encompasses pharmaceutical compositionscontaining, and methods of treating disorders through administering,pharmaceutically acceptable prodrugs of bifunctional compounds of theapplication. For example, compounds of the application having freeamino, amido, hydroxy or carboxylic groups can be converted intoprodrugs. Prodrugs include compounds wherein an amino acid residue, or apolypeptide chain of two or more (e.g., two, three or four) amino acidresidues is covalently joined through an amide or ester bond to a freeamino, hydroxy or carboxylic acid group of compounds of the application.The amino acid residues include but are not limited to the 20 naturallyoccurring amino acids commonly designated by three letter symbols andalso includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline, homocysteine, homoserine, ornithine and methionine sulfone.Additional types of prodrugs are also encompassed. For instance, freecarboxyl groups can be derivatized as amides or alkyl esters. Freehydroxy groups may be derivatized using groups including but not limitedto hemisuccinates, phosphate esters, dimethylaminoacetates, andphosphoryloxymethyloxy carbonyls, as outlined in Advanced Drug DeliveryReviews, 1996, 19, 1 15. Carbamate prodrugs of hydroxy and amino groupsare also included, as are carbonate prodrugs, sulfonate esters andsulfate esters of hydroxy groups. Derivatization of hydroxy groups as(acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group may bean alkyl ester, optionally substituted with groups including but notlimited to ether, amine and carboxylic acid functionalities, or wherethe acyl group is an amino acid ester as described above, are alsoencompassed. Prodrugs of this type are described in J. Med. Chem. 1996,39, 10. Free amines can also be derivatized as amides, sulfonamides orphosphonamides. All of these prodrug moieties may incorporate groupsincluding but not limited to ether, amine and carboxylic acidfunctionalities.

The application also provides for a pharmaceutical compositioncomprising a therapeutically effective amount of a bifunctional compoundof the application, or an enantiomer, diastereomer, stereoisomer, orpharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

In another aspect, the application provides a kit comprising abifunctional compound capable of inhibiting BTK activity selected fromone or more compounds disclosed herein, or a pharmaceutically acceptablesalt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof,optionally in combination with a second agent and instructions for usein treating cancer.

In another aspect, the application provides a method of synthesizing abifunctional compound disclosed herein.

The synthesis of the bifunctional compounds of the application can befound herein and in the Examples below.

Other embodiments are a method of making a bifunctional compound of anyof the formulae herein using any one, or combination of, reactionsdelineated herein. The method can include the use of one or moreintermediates or chemical reagents delineated herein.

Another aspect is an isotopically labeled bifunctional compound of anyof the formulae delineated herein. Such compounds have one or moreisotope atoms which may or may not be radioactive (e.g., ³H, ²H, ¹⁴C,¹³C, ¹⁸F, ³⁵S, ³²P, ¹²⁵I, and ¹³¹I) introduced into the bifunctionalcompound. Such compounds are useful for drug metabolism studies anddiagnostics, as well as therapeutic applications.

A bifunctional compound of the application can be prepared as apharmaceutically acceptable acid addition salt by reacting the free baseform of the compound with a pharmaceutically acceptable inorganic ororganic acid. Alternatively, a pharmaceutically acceptable base additionsalt of a bifunctional compound of the application can be prepared byreacting the free acid form of the bifunctional compound with apharmaceutically acceptable inorganic or organic base.

Alternatively, the salt forms of the bifunctional compounds of theapplication can be prepared using salts of the starting materials orintermediates.

The free acid or free base forms of the bifunctional compounds of theapplication can be prepared from the corresponding base addition salt oracid addition salt from, respectively. For example, a bifunctionalcompound of the application in an acid addition salt form can beconverted to the corresponding free base by treating with a suitablebase (e.g., ammonium hydroxide solution, sodium hydroxide, and thelike). A bifunctional compound of the application in a base additionsalt form can be converted to the corresponding free acid by treatingwith a suitable acid (e.g., hydrochloric acid, etc.).

Prodrugs of the bifunctional compounds of the application can beprepared by methods known to those of ordinary skill in the art (e.g.,for further details see Saulnier et al., (1994), Bioorganic andMedicinal Chemistry Letters, Vol. 4, p. 1985). For example, appropriateprodrugs can be prepared by reacting a non-derivatized bifunctionalcompound of the application with a suitable carbamylating agent (e.g.,1,1-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or thelike).

Protected derivatives of the bifunctional compounds of the applicationcan be made by means known to those of ordinary skill in the art. Adetailed description of techniques applicable to the creation ofprotecting groups and their removal can be found in T. W. Greene,“Protecting Groups in Organic Chemistry”, 3rd edition, John Wiley andSons, Inc., 1999.

Compounds of the present application can be conveniently prepared orformed during the process of the application, as solvates (e.g.,hydrates). Hydrates of bifunctional compounds of the present applicationcan be conveniently prepared by recrystallization from anaqueous/organic solvent mixture, using organic solvents such as dioxin,tetrahydrofuran or methanol.

Acids and bases useful in the methods herein are known in the art. Acidcatalysts are any acidic chemical, which can be inorganic (e.g.,hydrochloric, sulfuric, nitric acids, aluminum trichloride) or organic(e.g., camphorsulfonic acid, p-toluenesulfonic acid, acetic acid,ytterbium triflate) in nature. Acids are useful in either catalytic orstoichiometric amounts to facilitate chemical reactions. Bases are anybasic chemical, which can be inorganic (e.g., sodium bicarbonate,potassium hydroxide) or organic (e.g., triethylamine, pyridine) innature. Bases are useful in either catalytic or stoichiometric amountsto facilitate chemical reactions.

Combinations of substituents and variables envisioned by thisapplication are only those that result in the formation of stablecompounds. The term “stable”, as used herein, refers to compounds whichpossess stability sufficient to allow manufacture and which maintainsthe integrity of the compound for a sufficient period of time to beuseful for the purposes detailed herein (e.g., therapeutic orprophylactic administration to a subject).

When any variable (e.g., R₁₄) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with one or more R₁₄moieties, then R₁₄ at each occurrence is selected independently from thedefinition of R₁₄. Also, combinations of substituents and/or variablesare permissible, but only if such combinations result in stablecompounds within a designated atom's normal valency.

In addition, some of the compounds of this application have one or moredouble bonds, or one or more asymmetric centers. Such compounds canoccur as racemates, racemic mixtures, single enantiomers, individualdiastereomers, diastereomeric mixtures, and cis- or trans- or E- orZ-double isomeric forms, and other stereoisomeric forms that may bedefined, in terms of absolute stereochemistry, as (R)- or (S)-, or as(D)- or (L)- for amino acids. When the compounds described hereincontain olefinic double bonds or other centers of geometric asymmetry,and unless specified otherwise, it is intended that the compoundsinclude both E and Z geometric isomers. The configuration of anycarbon-carbon double bond appearing herein is selected for convenienceonly and is not intended to designate a particular configuration unlessthe text so states; thus a carbon-carbon double bond depictedarbitrarily herein as trans may be cis, trans, or a mixture of the twoin any proportion. All such isomeric forms of such compounds areexpressly included in the present application.

Optical isomers may be prepared from their respective optically activeprecursors by the procedures described herein, or by resolving theracemic mixtures. The resolution can be carried out in the presence of aresolving agent, by chromatography or by repeated crystallization or bysome combination of these techniques which are known to those skilled inthe art. Further details regarding resolutions can be found in Jacques,et al., Enantiomers, Racemates, and Resolutions (John Wiley & Sons,1981).

“Isomerism” means compounds that have identical molecular formulae butdiffer in the sequence of bonding of their atoms or in the arrangementof their atoms in space. Isomers that differ in the arrangement of theiratoms in space are termed “stereoisomers”. Stereoisomers that are notmirror images of one another are termed “diastereoisomers”, andstereoisomers that are non-superimposable mirror images of each otherare termed “enantiomers” or sometimes optical isomers. A mixturecontaining equal amounts of individual enantiomeric forms of oppositechirality is termed a “racemic mixture”.

A carbon atom bonded to four non-identical substituents is termed a“chiral center”.

“Chiral isomer” means a compound with at least one chiral center.Compounds with more than one chiral center may exist either as anindividual diastereomer or as a mixture of diastereomers, termed“diastereomeric mixture”. When one chiral center is present, astereoisomer may be characterized by the absolute configuration (R or S)of that chiral center. Absolute configuration refers to the arrangementin space of the substituents attached to the chiral center. Thesubstituents attached to the chiral center under consideration areranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog.(Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahnet al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951(London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem.Educ. 1964, 41, 116).

“Geometric isomer” means the diastereomers that owe their existence tohindered rotation about double bonds. These configurations aredifferentiated in their names by the prefixes cis and trans, or Z and E,which indicate that the groups are on the same or opposite side of thedouble bond in the molecule according to the Cahn-Ingold-Prelog rules.

Furthermore, the structures and other compounds discussed in thisapplication include all atropic isomers thereof. “Atropic isomers” are atype of stereoisomer in which the atoms of two isomers are arrangeddifferently in space. Atropic isomers owe their existence to arestricted rotation caused by hindrance of rotation of large groupsabout a central bond. Such atropic isomers typically exist as a mixture,however as a result of recent advances in chromatography techniques; ithas been possible to separate mixtures of two atropic isomers in selectcases.

“Tautomer” is one of two or more structural isomers that exist inequilibrium and is readily converted from one isomeric form to another.This conversion results in the formal migration of a hydrogen atomaccompanied by a switch of adjacent conjugated double bonds. Tautomersexist as a mixture of a tautomeric set in solution. In solid form,usually one tautomer predominates. In solutions where tautomerization ispossible, a chemical equilibrium of the tautomers will be reached. Theexact ratio of the tautomers depends on several factors, includingtemperature, solvent and pH. The concept of tautomers that areinterconvertable by tautomerizations is called tautomerism.

Of the various types of tautomerism that are possible, two are commonlyobserved. In keto-enol tautomerism a simultaneous shift of electrons anda hydrogen atom occurs. Ring-chain tautomerism arises as a result of thealdehyde group (—CHO) in a sugar chain molecule reacting with one of thehydroxy groups (—OH) in the same molecule to give it a cyclic(ring-shaped) form as exhibited by glucose. Common tautomeric pairs are:ketone-enol, amide-nitrile, lactam-lactim, amide-imidic acid tautomerismin heterocyclic rings (e.g., in nucleobases such as guanine, thymine andcytosine), amine-enamine and enamine-enamine. The compounds of thisapplication may also be represented in multiple tautomeric forms, insuch instances, the application expressly includes all tautomeric formsof the compounds described herein (e.g., alkylation of a ring system mayresult in alkylation at multiple sites, the application expresslyincludes all such reaction products).

In the present application, the structural formula of the bifunctionalcompound represents a certain isomer for convenience in some cases, butthe present application includes all isomers, such as geometricalisomers, optical isomers based on an asymmetrical carbon, stereoisomers,tautomers, and the like. In the present specification, the structuralformula of the compound represents a certain isomer for convenience insome cases, but the present application includes all isomers, such asgeometrical isomers, optical isomers based on an asymmetrical carbon,stereoisomers, tautomers, and the like.

Additionally, the compounds of the present application, for example, thesalts of the bifunctional compounds, can exist in either hydrated orunhydrated (the anhydrous) form or as solvates with other solventmolecules. Non-limiting examples of hydrates include monohydrates,dihydrates, etc. Non-limiting examples of solvates include ethanolsolvates, acetone solvates, etc.

“Solvate” means solvent addition forms that contain eitherstoichiometric or non stoichiometric amounts of solvent. Some compoundshave a tendency to trap a fixed molar ratio of solvent molecules in thecrystalline solid state, thus forming a solvate. If the solvent is waterthe solvate formed is a hydrate; and if the solvent is alcohol, thesolvate formed is an alcoholate. Hydrates are formed by the combinationof one or more molecules of water with one molecule of the substance inwhich the water retains its molecular state as H₂O.

The synthesized bifunctional compounds can be separated from a reactionmixture and further purified by a method such as column chromatography,high pressure liquid chromatography, or recrystallization. As can beappreciated by the skilled artisan, further methods of synthesizing thebifunctional compounds of the formulae herein will be evident to thoseof ordinary skill in the art. Additionally, the various synthetic stepsmay be performed in an alternate sequence or order to give the desiredcompounds. In addition, the solvents, temperatures, reaction durations,etc. delineated herein are for purposes of illustration only and one ofordinary skill in the art will recognize that variation of the reactionconditions can produce the desired bridged macrocyclic products of thepresent application. Synthetic chemistry transformations and protectinggroup methodologies (protection and deprotection) useful in synthesizingthe compounds described herein are known in the art and include, forexample, those such as described in R. Larock, Comprehensive OrganicTransformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons(1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995), and subsequent editions thereof.

The compounds of this application may be modified by appending variousfunctionalities via any synthetic means delineated herein to enhanceselective biological properties. Such modifications are known in the artand include those which increase biological penetration into a givenbiological system (e.g., blood, lymphatic system, central nervoussystem), increase oral availability, increase solubility to allowadministration by injection, alter metabolism and alter rate ofexcretion.

The compounds of the application are defined herein by their chemicalstructures and/or chemical names. Where a compound is referred to byboth a chemical structure and a chemical name, and the chemicalstructure and chemical name conflict, the chemical structure isdeterminative of the compound's identity.

The recitation of a listing of chemical groups in any definition of avariable herein includes definitions of that variable as any singlegroup or combination of listed groups. The recitation of an embodimentfor a variable herein includes that embodiment as any single embodimentor in combination with any other embodiments or portions thereof.

Method of Synthesizing the Compounds

Compounds of the present application can be prepared in a variety ofways using commercially available starting materials, compounds known inthe literature, or from readily prepared intermediates, by employingstandard synthetic methods and procedures either known to those skilledin the art, or which will be apparent to the skilled artisan in light ofthe teachings herein. Standard synthetic methods and procedures for thepreparation of organic molecules and functional group transformationsand manipulations can be obtained from the relevant scientificliterature or from standard textbooks in the field. Although not limitedto any one or several sources, classic texts such as Smith, M. B.,March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms,and Structure, 5^(th) edition, John Wiley & Sons: New York, 2001; andGreene, T. W., Wuts, P. G. M., Protective Groups in Organic Synthesis,3^(rd) edition, John Wiley & Sons: New York, 1999, incorporated byreference herein, are useful and recognized reference textbooks oforganic synthesis known to those in the art. The following descriptionsof synthetic methods are designed to illustrate, but not to limit,general procedures for the preparation of compounds of the presentapplication. The processes generally provide the desired final compoundat or near the end of the overall process, although it may be desirablein certain instances to further convert the compound to apharmaceutically acceptable salt, ester or prodrug thereof. Suitablesynthetic routes are depicted in the schemes below.

Those skilled in the art will recognize if a stereocenter exists in thecompounds disclosed herein. Accordingly, the present applicationincludes both possible stereoisomers (unless specified in the synthesis)and includes not only racemic compounds but the individual enantiomersand/or diastereomers as well. When a compound is desired as a singleenantiomer or diastereomer, it may be obtained by stereospecificsynthesis or by resolution of the final product or any convenientintermediate. Resolution of the final product, an intermediate, or astarting material may be affected by any suitable method known in theart. See, for example, “Stereochemistry of Organic Compounds” by E. L.Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994).

The compounds of the present application can be prepared in a number ofways well known to those skilled in the art of organic synthesis. By wayof example, compounds of the present application can be synthesizedusing the methods described below, together with synthetic methods knownin the art of synthetic organic chemistry, or variations thereon asappreciated by those skilled in the art. Preferred methods include butare not limited to those methods described below.

Compounds of the present application can be synthesized by following thesteps outlined in General Scheme 1 and 2 which comprise differentsequences of assembling intermediates. Starting materials are eithercommercially available or made by known procedures in the reportedliterature or as illustrated.

wherein R₂₈, R₂₉, R₃₀, R₃₁, W, p1, q, and v are as defined herein above.

The general way of preparing representative compounds of the presentapplication (i.e., Compound of formula (I) shown above) usingintermediates 1a, 1b, 1c, 1d, 1e, 1f, and 1g is outlined in GeneralScheme 1. Reaction of 1a with 1b in the presence of a base, i.e.,diisopropylethylamine (DIPEA), and in a solvent, i.e., dimethylformamide(DMF), provides intermediate 1c. Reaction of 1d with fluoride 1cprovides intermediate 1e. Deprotection of the 1e in the presence of TFAin a solvent, i.e., dichloromethane (DCM) or methanol (MeOH), provides1f. Coupling of 1f and Target Ligand (TL) 1g under standard couplingconditions using a coupling reagent, i.e.,1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI) andhydroxybenzotriazole, in a solvent, i.e., DCM or DMF, providesbifunctional compound of formula (I).

The general way of preparing representative compounds of the presentapplication (i.e., Compound of formula (II) shown above) usingintermediates 3a, 3b, 3c, and 3d is outlined in General Scheme 2.Reaction of 3a with 3b in the presence of potassium iodide (KI), a base,i.e., potassium carbonate (K₂CO₃), and in a solvent, i.e., acetone),followed by Boc deprotection in the presence of strong acid (i.e.,hydrochloric acid (HCl) or trifluoroacetic acid (TFA)) in a solvent,i.e., dichloromethane (DCM) or methanol (MeOH) provides intermediate 3c.Coupling of amine 3d and Target Ligand 3c under standard couplingconditions using a coupling reagent, i.e.,1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI) andhydroxybenzotriazole (HOBt), and a base (i.e., triethylamine (TEA)) in asolvent, i.e., DCM or DMF, provides bifunctional compound of formula(II) in shown in General Scheme 2.

Biological Assays

Cell Viability Assay

Wild-type or cereblon null cells are treated with various concentrationsof a bifunctional compound of the application and allowed to grow. Cellsare then assayed to determine cell viability by measuring the amount ofATP present, which is an indicator of cell metabolic activity. Resultsare graphed as relative luminescent values.

Methods of the Application

In another aspect, the application provides a method of modulating akinase, comprising contacting the kinase with a bifunctional compounddisclosed herein, or an enantiomer, diastereomer, or stereoisomerthereof, or pharmaceutically acceptable salt, hydrate, solvate, orprodrug thereof, or with a pharmaceutical composition disclosed herein.In some embodiments, the kinase is BTK.

In another aspect, the application provides a method of inhibiting akinase, comprising contacting the kinase with a bifunctional compounddisclosed herein, or an enantiomer, diastereomer, or stereoisomerthereof, or pharmaceutically acceptable salt, hydrate, solvate, orprodrug thereof, or with a pharmaceutical composition disclosed herein.In some embodiments, the kinase is BTK.

In still another aspect, the application provides a method of inhibitingBTK, the method comprising administering to a subject in need thereof aneffective amount of a bifunctional compound disclosed herein, or anenantiomer, diastereomer, or stereoisomer thereof, or pharmaceuticallyacceptable salt, hydrate, solvate, or prodrug thereof.

In still another aspect, the application provides a method of inhibitingBTK, the method comprising administering to a subject in need thereof aneffective amount of a pharmaceutical composition comprising abifunctional compound disclosed herein, or an enantiomer, diastereomer,or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate,solvate, or prodrug thereof and a pharmaceutically acceptable carrier.

Another aspect of the application provides a method of treating orpreventing a disease, the method comprising administering to a subjectin need thereof an effective amount of a bifunctional compound disclosedherein, or an enantiomer, diastereomer, or stereoisomer thereof, orpharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.In some embodiments, the disease is mediated by a kinase. In furtherembodiments, the kinase is BTK.

Another aspect of the application provides a method of treating orpreventing a disease, the method comprising administering to a subjectin need thereof an effective amount of a pharmaceutical compositioncomprising a bifunctional compound disclosed herein, or an enantiomer,diastereomer, or stereoisomer thereof, or pharmaceutically acceptablesalt, hydrate, solvate, or prodrug thereof and a pharmaceuticallyacceptable carrier. In some embodiments, the disease is mediated by akinase. In further embodiments, the kinase is BTK.

In some embodiments, the disease is mediated by BTK (e.g., BTK plays arole in the initiation or development of the disease).

In certain embodiments, the disease or disorder is cancer or aproliferation disease.

In further embodiments, the disease or disorder is lung cancer, coloncancer, breast cancer, prostate cancer, liver cancer, pancreas cancer,brain cancer, kidney cancer, ovarian cancer, stomach cancer, skincancer, bone cancer, gastric cancer, breast cancer, pancreatic cancer,glioma, glioblastoma, hepatocellular carcinoma, papillary renalcarcinoma, head and neck squamous cell carcinoma, leukemias, lymphomas,myelomas, or solid tumors.

In further embodiments, the disease or disorder is sarcoma. In furtherembodiments, the disease or disorder is sarcoma of the bones, muscles,tendons, cartilage, nerves, fat, or blood vessels. In furtherembodiments, the disease or disorder is soft tissue sarcoma, bonesarcoma, or osteosarcoma. In further embodiments, the disease ordisorder is angiosarcoma, fibrosarcoma, liposarcoma, leiomyosarcoma,Karposi's sarcoma, osteosarcoma, gastrointestinal stromal tumor,Synovial sarcoma, Pleomorphic sarcoma, chondrosarcoma, Ewing's sarcoma,reticulum cell sarcoma, meningiosarcoma, botryoid sarcoma,rhabdomyosarcoma, or embryonal rhabdomyosarcoma.

In further embodiments, the disease or disorder is multiple myeloma.

In other embodiments, the disease or disorder is inflammation,arthritis, rheumatoid arthritis, spondyiarthropathies, gouty arthritis,osteoarthritis, juvenile arthritis, and other arthritic conditions,systemic lupus erythematosus (SLE), skin-related conditions, psoriasis,eczema, burns, dermatitis, neuroinflammation, allergy, pain, neuropathicpain, fever, pulmonary disorders, lung inflammation, adult respiratorydistress syndrome, pulmonary sarcoidosis, asthma, silicosis, chronicpulmonary inflammatory disease, and chronic obstructive pulmonarydisease (COPD), cardiovascular disease, arteriosclerosis, myocardialinfarction (including post-myocardial infarction indications),thrombosis, congestive heart failure, cardiac reperfusion injury, aswell as complications associated with hypertension and/or heart failuresuch as vascular organ damage, restenosis, cardiomyopathy, strokeincluding ischemic and hemorrhagic stroke, reperfusion injury, renalreperfusion injury, ischemia including stroke and brain ischemia, andischemia resulting from cardiac/coronary bypass, neurodegenerativedisorders, liver disease and nephritis, gastrointestinal conditions,inflammatory bowel disease, Crohn's disease, gastritis, irritable bowelsyndrome, ulcerative colitis, ulcerative diseases, gastric ulcers, viraland bacterial infections, sepsis, septic shock, gram negative sepsis,malaria, meningitis, HIV infection, opportunistic infections, cachexiasecondary to infection or malignancy, cachexia secondary to acquiredimmune deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex),pneumonia, herpes virus, myalgias due to infection, influenza,autoimmune disease, graft vs. host reaction and allograft rejections,treatment of bone resorption diseases, osteoporosis, multiple sclerosis,cancer, leukemia, lymphoma, colorectal cancer, brain cancer, bonecancer, epithelial call-derived neoplasia (epithelial carcinoma), basalcell carcinoma, adenocarcinoma, gastrointestinal cancer, lip cancer,mouth cancer, esophageal cancer, small bowel cancer, stomach cancer,colon cancer, liver cancer, bladder cancer, pancreas cancer, ovariancancer, cervical cancer, lung cancer, breast cancer, skin cancer,squamous cell and/or basal cell cancers, prostate cancer, renal cellcarcinoma, and other known cancers that affect epithelial cellsthroughout the body, chronic myelogenous leukemia (CML), acute myeloidleukemia (AML) and acute promyelocytic leukemia (APL), angiogenesisincluding neoplasia, metastasis, central nervous system disorders,central nervous system disorders having an inflammatory or apoptoticcomponent, Alzheimer's disease, Parkinson's disease, Huntington'sdisease, amyotrophic lateral sclerosis, spinal cord injury, andperipheral neuropathy, or B-Cell Lymphoma.

In further embodiments, the disease or disorder is inflammation,arthritis, rheumatoid arthritis, spondylarthropathies, gouty arthritis,osteoarthritis, juvenile arthritis, and other arthritic conditions,systemic lupus erythematosus (SLE), skin-related conditions, psoriasis,eczema, dermatitis, pain, pulmonary disorders, lung inflammation, adultrespiratory distress syndrome, pulmonary sarcoidosis, asthma, chronicpulmonary inflammatory disease, and chronic obstructive pulmonarydisease (COPD), cardiovascular disease, arteriosclerosis, myocardialinfarction (including post-myocardial infarction indications),congestive heart failure, cardiac reperfusion injury, inflammatory boweldisease, Crohn's disease, gastritis, irritable bowel syndrome, leukemiaor lymphoma.

Another aspect of the application provides a method of treating a kinasemediated disorder, the method comprising administering to a subject inneed thereof an effective amount of a bifunctional compound disclosedherein, or an enantiomer, diastereomer, or stereoisomer thereof, orpharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.In some embodiments, the bifunctional compound is an inhibitor of BTK.In other embodiments, the subject is administered an additionaltherapeutic agent. In other embodiments, the bifunctional compound andthe additional therapeutic agent are administered simultaneously orsequentially.

Another aspect of the application provides a method of treating a kinasemediated disorder, the method comprising administering to a subject inneed thereof an effective amount of a pharmaceutical compositioncomprising a bifunctional compound disclosed herein, or an enantiomer,diastereomer, or stereoisomer thereof, or pharmaceutically acceptablesalt, hydrate, solvate, or prodrug thereof and a pharmaceuticallyacceptable carrier. In some embodiments, the bifunctional compound is aninhibitor of BTK. In other embodiments, the subject is administered anadditional therapeutic agent. In other embodiments, the pharmaceuticalcomposition comprising a bifunctional compound and the additionaltherapeutic agent are administered simultaneously or sequentially.

In other embodiments, the disease or disorder is cancer. In furtherembodiments, the cancer is lung cancer, colon cancer, breast cancer,prostate cancer, liver cancer, pancreas cancer, brain cancer, kidneycancer, ovarian cancer, stomach cancer, skin cancer, bone cancer,gastric cancer, breast cancer, pancreatic cancer, glioma, glioblastoma,hepatocellular carcinoma, papillary renal carcinoma, head and necksquamous cell carcinoma, leukemias, lymphomas, myelomas, or solidtumors.

Another aspect of the present application relates to a method oftreating or preventing a proliferative disease. The method comprisesadministering to a subject in need thereof an effective amount of abifunctional compound of the application, or an enantiomer,diastereomer, or stereoisomer thereof, or pharmaceutically acceptablesalt, hydrate, solvate, or prodrug thereof.

Another aspect of the present application relates to a method oftreating or preventing a proliferative disease. The method comprisesadministering to a subject in need thereof an effective amount of apharmaceutical composition comprising a bifunctional compound disclosedherein, or an enantiomer, diastereomer, or stereoisomer thereof, orpharmaceutically acceptable salt, hydrate, solvate, or prodrug thereofand a pharmaceutically acceptable carrier.

In another aspect, the application provides a method of treating orpreventing cancer, wherein the cancer cell comprises activated BTK,comprising administering to a subject in need thereof an effectiveamount of a bifunctional compound disclosed herein, or an enantiomer,diastereomer, or stereoisomer thereof, or pharmaceutically acceptablesalt, hydrate, solvate, or prodrug thereof.

In another aspect, the application provides a method of treating orpreventing cancer, wherein the cancer cell comprises activated BTK,comprising administering to a subject in need thereof an effectiveamount of a pharmaceutical composition comprising a bifunctionalcompound disclosed herein, or an enantiomer, diastereomer, orstereoisomer thereof, or pharmaceutically acceptable salt, hydrate,solvate, or prodrug thereof and a pharmaceutically acceptable carrier.

In certain embodiments, the BTK activation is selected from mutation ofBTK, amplification of BTK, expression of BTK, and ligand mediatedactivation of BTK.

Another aspect of the application provides a method of treating orpreventing cancer in a subject, wherein the subject is identified asbeing in need of BTK inhibition for the treatment of cancer, comprisingadministering to the subject an effective amount of a bifunctionalcompound disclosed herein, or an enantiomer, diastereomer, orstereoisomer thereof, or pharmaceutically acceptable salt, hydrate,solvate, or prodrug thereof.

Another aspect of the application provides a method of treating orpreventing cancer in a subject, wherein the subject is identified asbeing in need of BTK inhibition for the treatment of cancer, comprisingadministering to the subject an effective amount of a pharmaceuticalcomposition comprising a bifunctional compound disclosed herein, or anenantiomer, diastereomer, or stereoisomer thereof, or pharmaceuticallyacceptable salt, hydrate, solvate, or prodrug thereof and apharmaceutically acceptable carrier.

In certain embodiments, the application provides a method of treatingany of the disorders described herein, wherein the subject is a human.In certain embodiments, the application provides a method of preventingany of the disorders described herein, wherein the subject is a human.

In another aspect, the application provides a bifunctional compounddisclosed herein, or an enantiomer, diastereomer, or stereoisomerthereof, or pharmaceutically acceptable salt, hydrate, solvate, orprodrug thereof, for use in the manufacture of a medicament for treatingor preventing a disease in which BTK plays a role.

In still another aspect, the application provides a bifunctionalcompound of the application, or an enantiomer, diastereomer, orstereoisomer thereof, or pharmaceutically acceptable salt, hydrate,solvate, or prodrug thereof for use in treating or preventing a diseasein which BTK plays a role.

In another aspect, the application provides a pharmaceutical compositioncomprising a bifunctional compound disclosed herein, or an enantiomer,diastereomer, or stereoisomer thereof, or pharmaceutically acceptablesalt, hydrate, solvate, or prodrug thereof f and a pharmaceuticallyacceptable carrier, for use in the manufacture of a medicament fortreating or preventing a disease in which BTK plays a role.

In still another aspect, the application provides a pharmaceuticalcomposition comprising a bifunctional compound disclosed herein, or anenantiomer, diastereomer, or stereoisomer thereof, or pharmaceuticallyacceptable salt, hydrate, solvate, or prodrug thereof and apharmaceutically acceptable carrier, for use in treating or preventing adisease in which BTK plays a role.

As inhibitors of BTK, the bifunctional compounds and compositions ofthis application are particularly useful for treating or lessening theseverity of a disease, condition, or disorder where a protein kinase isimplicated in the disease, condition, or disorder. In one aspect, thepresent application provides a method for treating or lessening theseverity of a disease, condition, or disorder where a protein kinase isimplicated in the disease state. In another aspect, the presentapplication provides a method for treating or lessening the severity ofa protein kinase mediated disease, condition, or disorder whereinhibition of enzymatic activity is implicated in the treatment of thedisease. In another aspect, this application provides a method fortreating or lessening the severity of a disease, condition, or disorderwith bifunctional compounds that inhibit enzymatic activity by bindingto the protein kinase. Another aspect provides a method for treating orlessening the severity of a protein kinase mediated disease, condition,or disorder by inhibiting enzymatic activity of the protein kinase witha protein kinase inhibitor.

In some embodiments, said method is used to treat or prevent a conditionselected from autoimmune diseases, inflammatory diseases, proliferativeand hyperproliferative diseases, immunologically-mediated diseases, bonediseases, metabolic diseases, neurological and neurodegenerativediseases, cardiovascular diseases, hormone related diseases, allergies,asthma, and Alzheimer's disease. In other embodiments, said condition isselected from a proliferative disorder and a neurodegenerative disorder.

One aspect of this application provides bifunctional compounds that areuseful for the treatment of diseases, disorders, and conditionscharacterized by excessive or abnormal cell proliferation. Such diseasesinclude, but are not limited to, a proliferative or hyperproliferativedisease, and a neurodegenerative disease. Examples of proliferative andhyperproliferative diseases include, without limitation, cancer. Theterm “cancer” includes, but is not limited to, the following cancers:breast; ovary; cervix; prostate; testis, genitourinary tract; esophagus;larynx, glioblastoma; neuroblastoma; stomach; skin, keratoacanthoma;lung, epidermoid carcinoma, large cell carcinoma, small cell carcinoma,lung adenocarcinoma; bone; colon; colorectal; adenoma; pancreas,adenocarcinoma; thyroid, follicular carcinoma, undifferentiatedcarcinoma, papillary carcinoma; seminoma; melanoma; sarcoma; bladdercarcinoma; liver carcinoma and biliary passages; kidney carcinoma;myeloid disorders; lymphoid disorders, Hodgkin's, hairy cells; buccalcavity and pharynx (oral), lip, tongue, mouth, pharynx; small intestine;colonrectum, large intestine, rectum, brain and central nervous system;chronic myeloid leukemia (CML), and leukemia. The term “cancer”includes, but is not limited to, the following cancers: myeloma,lymphoma, or a cancer selected from gastric, renal, or and the followingcancers: head and neck, oropharyngeal, non-small cell lung cancer(NSCLC), endometrial, hepatocarcinoma, Non-Hodgkins lymphoma, andpulmonary.

The term “cancer” refers to any cancer caused by the proliferation ofmalignant neoplastic cells, such as tumors, neoplasms, carcinomas,sarcomas, leukemias, lymphomas and the like. For example, cancersinclude, but are not limited to, mesothelioma, leukemias and lymphomassuch as cutaneous T-cell lymphomas (CTCL), noncutaneous peripheralT-cell lymphomas, lymphomas associated with human T-cell lymphotrophicvirus (HTLV) such as adult T-cell leukemia/lymphoma (ATLL), B-celllymphoma, acute nonlymphocytic leukemias, chronic lymphocytic leukemia,chronic myelogenous leukemia, acute myelogenous leukemia, lymphomas, andmultiple myeloma, non-Hodgkin lymphoma, acute lymphatic leukemia (ALL),chronic lymphatic leukemia (CLL), Hodgkin's lymphoma, Burkitt lymphoma,adult T-cell leukemia lymphoma, acute-myeloid leukemia (AML), chronicmyeloid leukemia (CML), or hepatocellular carcinoma. Further examplesinclude myelodysplastic syndrome, childhood solid tumors such as braintumors, neuroblastoma, retinoblastoma, Wilms' tumor, bone tumors, andsoft-tissue sarcomas, common solid tumors of adults such as head andneck cancers (e.g., oral, laryngeal, nasopharyngeal and esophageal),genitourinary cancers (e.g., prostate, bladder, renal, uterine, ovarian,testicular), lung cancer (e.g., small-cell and non-small cell), breastcancer, pancreatic cancer, melanoma and other skin cancers, stomachcancer, brain tumors, tumors related to Gorlin's syndrome (e.g.,medulloblastoma, meningioma, etc.), and liver cancer. Additionalexemplary forms of cancer which may be treated by the subjectbifunctional compounds include, but are not limited to, cancer ofskeletal or smooth muscle, stomach cancer, cancer of the smallintestine, rectum carcinoma, cancer of the salivary gland, endometrialcancer, adrenal cancer, anal cancer, rectal cancer, parathyroid cancer,and pituitary cancer.

Additional cancers that the bifunctional compounds described herein maybe useful in preventing, treating and studying are, for example, coloncarcinoma, familiary adenomatous polyposis carcinoma and hereditarynon-polyposis colorectal cancer, or melanoma. Further, cancers include,but are not limited to, labial carcinoma, larynx carcinoma, hypopharynxcarcinoma, tongue carcinoma, salivary gland carcinoma, gastriccarcinoma, adenocarcinoma, thyroid cancer (medullary and papillarythyroid carcinoma), renal carcinoma, kidney parenchyma carcinoma, cervixcarcinoma, uterine corpus carcinoma, endometrium carcinoma, chorioncarcinoma, testis carcinoma, urinary carcinoma, melanoma, brain tumorssuch as glioblastoma, astrocytoma, meningioma, medulloblastoma andperipheral neuroectodermal tumors, gall bladder carcinoma, bronchialcarcinoma, multiple myeloma, basalioma, teratoma, retinoblastoma,choroidea melanoma, seminoma, rhabdomyosarcoma, craniopharyngeoma,osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma,Ewing sarcoma, and plasmocytoma. In one aspect of the application, thepresent application provides for the use of one or more bifunctionalcompounds of the application in the manufacture of a medicament for thetreatment of cancer, including without limitation the various types ofcancer disclosed herein.

In some embodiments, the bifunctional compounds of this application areuseful for treating cancer, such as colorectal, thyroid, breast, andlung cancer; and myeloproliferative disorders, such as polycythemiavera, thrombocythemia, myeloid metaplasia with myelofibrosis, chronicmyelogenous leukemia, chronic myelomonocytic leukemia, hypereosinophilicsyndrome, juvenile myelomonocytic leukemia, and systemic mast celldisease. In some embodiments, the bifunctional compounds of thisapplication are useful for treating hematopoietic disorders, inparticular, acute-myelogenous leukemia (AML), chronic-myelogenousleukemia (CML), acute-promyelocytic leukemia, and acute lymphocyticleukemia (ALL).

This application further embraces the treatment or prevention of cellproliferative disorders such as hyperplasias, dysplasias andpre-cancerous lesions. Dysplasia is the earliest form of pre-cancerouslesion recognizable in a biopsy by a pathologist. The subjectbifunctional compounds may be administered for the purpose of preventingsaid hyperplasias, dysplasias or pre-cancerous lesions from continuingto expand or from becoming cancerous. Examples of pre-cancerous lesionsmay occur in skin, esophageal tissue, breast and cervicalintra-epithelial tissue.

Another aspect of this application provides a method for the treatmentor lessening the severity of a disease selected from a proliferative orhyperproliferative disease, or a neurodegenerative disease, comprisingadministering an effective amount of a bifunctional compound, or apharmaceutically acceptable composition comprising a bifunctionalcompound, to a subject in need thereof.

As inhibitors of BTK kinase, the compounds and compositions of thisapplication are also useful in biological samples. One aspect of theapplication relates to inhibiting protein kinase activity in abiological sample, which method comprises contacting said biologicalsample with a bifunctional compound of the application or a compositioncomprising said bifunctional compound. The term “biological sample”, asused herein, means an in vitro or an ex vivo sample, including, withoutlimitation, cell cultures or extracts thereof; biopsied materialobtained from a mammal or extracts thereof; and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.Inhibition of protein kinase activity in a biological sample is usefulfor a variety of purposes that are known to one of skill in the art.Examples of such purposes include, but are not limited to, bloodtransfusion, organ-transplantation, and biological specimen storage.

Another aspect of this application relates to the study of BTK kinase inbiological and pathological phenomena; the study of intracellular signaltransduction pathways mediated by such protein kinases; and thecomparative evaluation of new protein kinase inhibitors. Examples ofsuch uses include, but are not limited to, biological assays such asenzyme assays and cell-based assays.

The activity of the compounds and compositions of the presentapplication as BTK inhibitors may be assayed in vitro, in vivo, or in acell line. In vitro assays include assays that determine inhibition ofeither the enzyme activity or ATPase activity of the activated kinase.Alternate in vitro assays quantitate the ability of the inhibitor tobind to the protein kinase and may be measured either by radio labellingthe inhibitor prior to binding, isolating the inhibitor/BTK complex anddetermining the amount of radio label bound, or by running a competitionexperiment where new inhibitors are incubated with the kinase bound toknown radioligands. Detailed conditions for assaying a compound utilizedin this application as an inhibitor of various kinases are set forth inthe Examples below.

In accordance with the foregoing, the present application furtherprovides a method for preventing or treating any of the diseases ordisorders described above in a subject in need of such treatment, whichmethod comprises administering to said subject a therapeuticallyeffective amount of a bifunctional compound of the application, or anenantiomer, diastereomer, or stereoisomer thereof, or pharmaceuticallyacceptable salt, hydrate, solvate, or prodrug thereof. For any of theabove uses, the required dosage will vary depending on the mode ofadministration, the particular condition to be treated and the effectdesired.

Pharmaceutical Compositions

In another aspect, the application provides a pharmaceutical compositioncomprising a therapeutically effective amount of a bifunctional compoundof the present application or an enantiomer, diastereomer, orstereoisomer thereof, or pharmaceutically acceptable salt, hydrate,solvate, or prodrug thereof, and a pharmaceutically acceptable carrier.

Bifunctional compounds of the application can be administered aspharmaceutical compositions by any conventional route, in particularenterally, e.g., orally, e.g., in the form of tablets or capsules, orparenterally, e.g., in the form of injectable solutions or suspensions,or topically, e.g., in the form of lotions, gels, ointments or creams,or in a nasal or suppository form. Pharmaceutical compositionscomprising a compound of the present application in free form or in apharmaceutically acceptable salt form in association with at least onepharmaceutically acceptable carrier or diluent can be manufactured in aconventional manner by mixing, granulating or coating methods. Forexample, oral compositions can be tablets or gelatin capsules comprisingthe active ingredient together with a) diluents, e.g., lactose,dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b)lubricants, e.g., silica, talcum, stearic acid, its magnesium or calciumsalt and/or polyethyleneglycol; for tablets also c) binders, e.g.,magnesium aluminum silicate, starch paste, gelatin, tragacanth,methylcellulose, sodium carboxymethylcellulose and orpolyvinylpyrrolidone; if desired d) disintegrants, e.g., starches, agar,alginic acid or its sodium salt, or effervescent mixtures; and/or e)absorbents, colorants, flavors and sweeteners. Injectable compositionscan be aqueous isotonic solutions or suspensions, and suppositories canbe prepared from fatty emulsions or suspensions. The compositions may besterilized and/or contain adjuvants, such as preserving, stabilizing,wetting or emulsifying agents, solution promoters, salts for regulatingthe osmotic pressure and/or buffers. In addition, they may also containother therapeutically valuable substances. Suitable formulations fortransdermal applications include an effective amount of a compound ofthe present application with a carrier. A carrier can include absorbablepharmacologically acceptable solvents to assist passage through the skinof the host. For example, transdermal devices are in the form of abandage comprising a backing member, a reservoir containing the compoundoptionally with carriers, optionally a rate controlling barrier todeliver the compound to the skin of the host at a controlled andpredetermined rate over a prolonged period of time, and means to securethe device to the skin. Matrix transdermal formulations may also beused. Suitable formulations for topical application, e.g., to the skinand eyes, are preferably aqueous solutions, ointments, creams or gelswell-known in the art. Such may contain solubilizers, stabilizers,tonicity enhancing agents, buffers and preservatives.

The pharmaceutical compositions of the present application comprise atherapeutically effective amount of a compound of the presentapplication formulated together with one or more pharmaceuticallyacceptable carriers. As used herein, the term “pharmaceuticallyacceptable carrier” means a non-toxic, inert solid, semi-solid or liquidfiller, diluent, encapsulating material or formulation auxiliary of anytype. Some examples of materials which can serve as pharmaceuticallyacceptable carriers include, but are not limited to, ion exchangers,alumina, aluminum stearate, lecithin, serum proteins, such as humanserum albumin, buffer substances such as phosphates, glycine, sorbicacid, or potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, polyacrylates, waxes, polyethylenepolyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose andsucrose; starches such as corn starch and potato starch; cellulose andits derivatives such as sodium carboxymethyl cellulose, ethyl celluloseand cellulose acetate; powdered tragacanth; malt; gelatin; talc;excipients such as cocoa butter and suppository waxes, oils such aspeanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; cornoil and soybean oil; glycols such a propylene glycol or polyethyleneglycol; esters such as ethyl oleate and ethyl laurate, agar; bufferingagents such as magnesium hydroxide and aluminum hydroxide; alginic acid;pyrogen-free water, isotonic saline; Ringer's solution; ethyl alcohol,and phosphate buffer solutions, as well as other non-toxic compatiblelubricants such as sodium lauryl sulfate and magnesium stearate, as wellas coloring agents, releasing agents, coating agents, sweetening,flavoring and perfuming agents, preservatives and antioxidants can alsobe present in the composition, according to the judgment of theformulator.

The pharmaceutical compositions of this application can be administeredto humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), buccally, or as an oral or nasal spray.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous, oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisapplication with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid compositions of a similar type may also be employed as fillers insoft and hard filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents.

Dosage forms for topical or transdermal administration of a compound ofthis application include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, eye ointments, powders and solutionsare also contemplated as being within the scope of this application.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this application, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisapplication, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants suchas chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispensing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

Compounds and compositions of the application can be administered intherapeutically effective amounts in a combinational therapy with one ormore therapeutic agents (pharmaceutical combinations) or modalities,e.g., an anti-proliferative, anti-cancer, immunomodulatory oranti-inflammatory agent. Where the compounds of the application areadministered in conjunction with other therapies, dosages of theco-administered compounds will of course vary depending on the type ofco-drug employed, on the specific drug employed, on the condition beingtreated and so forth. Compounds and compositions of the application canbe administered in therapeutically effective amounts in a combinationaltherapy with one or more therapeutic agents (pharmaceuticalcombinations) or modalities, e.g., anti-proliferative, anti-cancer,immunomodulatory or anti-inflammatory agent, and/or non-drug therapies,etc. For example, synergistic effects can occur with anti-proliferative,anti-cancer, immunomodulatory or anti-inflammatory substances. Where thecompounds of the application are administered in conjunction with othertherapies, dosages of the co-administered compounds will of course varydepending on the type of co-drug employed, on the specific drugemployed, on the condition being treated and so forth.

Combination therapy includes the administration of the subject compoundsin further combination with one or more other biologically activeingredients (such as, but not limited to, a second BTK inhibitor, asecond and different antineoplastic agent, a kinase inhibitor andnon-drug therapies (such as, but not limited to, surgery or radiationtreatment). For instance, the compounds of the application can be usedin combination with other pharmaceutically active compounds, preferablycompounds that are able to enhance the effect of the compounds of theapplication. The compounds of the application can be administeredsimultaneously (as a single preparation or separate preparation) orsequentially to the other drug therapy or treatment modality. Ingeneral, a combination therapy envisions administration of two or moredrugs during a single cycle or course of therapy.

In another aspect of the application, the compounds may be administeredin combination with one or more separate pharmaceutical agents, e.g., achemotherapeutic agent, an immunotherapeutic agent, or an adjunctivetherapeutic agent.

EXAMPLES

Analytical Methods, Materials, and Instrumentation

All reactions are monitored on a Waters Acquity UPLC/MS system (WatersPDA eλ Detector, QDa Detector, Sample manager—FL, Binary SolventManager) using Acquity UPLC® BEH C18 column (2.1×50 mm, 1.7 m particlesize): solvent gradient=90% A at 0 min, 1% A at 1.8 min; solvent A=0.1%formic acid in Water; solvent B=0.1% formic acid in Acetonitrile; flowrate: 0.6 mL/min. Reaction products are purified by flash columnchromatography using CombiFlash®Rf with Teledyne Isco RediSep®Rf HighPerformance Gold or Silicycle SiliaSep™ High Performance columns (4 g,12 g, 24 g, 40 g, or 80 g), Waters HPLC system using SunFire™ Prep C18column (19×100 mm, 5 m particle size): solvent gradient=80% A at 0 min,5% A at 25 min; solvent A=0.035% TFA in Water; solvent B=0.035% TFA inMeOH; flow rate: 25 mL/min (Method A), and Waters Acquity UPLC/MS system(Waters PDA eλ Detector, QDa Detector, Sample manager—FL, Binary SolventManager) using Acquity UPLC® BEH C18 column (2.1×50 mm, 1.7 μm particlesize): solvent gradient=80% A at 0 min, 5% A at 2 min; solvent A=0.1%formic acid in Water; solvent B=0.1% formic acid in Acetonitrile; flowrate: 0.6 mL/min (method B). The purity of all compounds is over 95% andis analyzed with Waters LC/MS system. ¹H NMR is obtained using a 500 MHzBruker Avance III. Chemical shifts are reported relative to dimethylsulfoxide (δ=2.50) for ¹H NMR. Data are reported as (br=broad,s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet).

Abbreviations used in the following examples and elsewhere herein are:

-   -   br broad    -   DCM dichloromethane    -   DMF N,N-dimethylformamide    -   DMSO dimethyl sulfoxide    -   EDCI 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide    -   ESI electrospray ionization    -   EtOAc ethyl acetate    -   HCl hydrochloric acid    -   h hour(s)    -   HPLC high-performance liquid chromatography    -   LCMS liquid chromatography-mass spectrometry    -   m multiplet    -   MeOH methanol    -   MHz megahertz    -   min minutes    -   MS mass spectrometry    -   NMR nuclear magnetic resonance    -   Pd(PPh₃)₄ tetrakis(triphenylphosphine)dipalladium(0)    -   ppm parts per million    -   TFA trifluoroacetic acid

Example 1: Synthesis of4-(tert-butyl)-N-(2-methyl-3-(4-methyl-5-oxo-6-((4-(piperazine-1-carbonyl)phenyl)amino)-4,5-dihydropyrazin-2-yl)phenyl)benzamidetrifluoroacetic acid Salt (Intermediate 2-1)

Step 1. tert-butyl 4-(4-nitrobenzoyl)piperazine-1-carboxylate (2c)

To a solution of tert-butyl piperazine-1-carboxylate (2a, 3.1 g, 16.6mmol, 1 equiv.), 4-nitrobenzoic acid (2b, 2.8 g, 16.6 mmol, 1 equiv.),N,N-diisopropylethylamine (5.8 mL, 33.2 mmol, 2 equiv.), andhydroxybenzotriazole (2.2 g, 16.6 mmol, 1 equiv.) in anhydrous DCM (40mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (3.8 g, 20.0 mmol, 1.2 equiv.) at 0° C. The resultingsolution was warmed to room temperature and then stirred for 24 h. Waterwas added and the mixture was extracted three times with DCM. Thecombined organic layers were dried with Na₂SO₄, filtered, andconcentrated. The resulting crude product was then purified via silicagel column chromatography to obtain the product 2c as a yellow solid(4.6 g, 13.7 mmol, 82% yield).

Step 2. Tert-butyl 4-(4-aminobenzoyl)piperazine-1-carboxylate (2d)

To a degassed solution of tert-butyl4-(4-nitrobenzoyl)piperazine-1-carboxylate (2c, 4.1 g, 12.3 mmol, 1equiv.) in anhydrous MeOH (40 mL) was added Pd/C (10% wt., dry; 600 mg).The reaction was sealed, fitted with a H₂ balloon and then stirred for 3h at room temperature. The reaction mixture was filtered through Celiteand then concentrated to obtain the product 2d as a white foam (3.7 g,12 mmol, 98% yield).

Step 3. tert-butyl4-(4-((6-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)benzoyl)piperazine-1-carboxylate(2f)

A solution of tert-butyl 4-(4-aminobenzoyl)piperazine-1-carboxylate (2d,1.7 g, 5.7 mmol, 1 equiv.), 3,5-dibromo-1-methylpyrazin-2(1H)-one (2e,1.8 g, 6.8 mmol, 1.2 equiv.) and N,N-diisopropylethylamine (1.48 mL, 8.5mmol, 1.5 equiv.) in N,N-dimethylacetamide (5 mL) was stirred in asealed vial at 105° C. for 30 h. The reaction was cooled to roomtemperature and EtOAc (20 mL) was then added. The solid precipitate wasfiltered and dried on high vacuum overnight to provide tert-butyl4-(4-((6-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)benzoyl)piperazine-1-carboxylate2f. The product was carried onto the next step without furtherpurification.

Step 4. Tert-butyl4-(4-((6-(3-amino-2-methylphenyl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)benzoyl)piperazine-1-carboxylate(2h)

Tert-butyl4-(4-((6-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)benzoyl)piperazine-1-carboxylate(2f, 1 g, 2.0 mmol, 1 equiv.) was dissolved in anhydrous 1,4-dioxane (6mL) and Na₂CO₃ (323 mg, 3.0 mmol, 1.5 equiv.) and H₂O (1.2 mL) wasadded. The mixture was degassed by bubbling N2 gas through the reactionsolution for 10 min. Pd(PPh₃)₄ (328 mg, 0.28 mmol, 0.14 equiv.) was thenadded and the vial was sealed and then stirred at 105° C. for 16 h. Theresulting mixture was cooled to r.t. and filtered through Celite. Thefiltrate was concentrated, the resulting residue was redissolved inEtOAc, and the organic layer was washed with saturated NaHCO₃(aq). Theorganic layer was dried with Na₂SO₄, filtered, and concentrated invacuo. The residue was purified via silica gel column chromatography toprovide the product 2h as a white solid (244 mg, 0.47 mmol, 27% yield).

Step 5.4-(tert-butyl)-N-(2-methyl-3-(4-methyl-5-oxo-6-((4-(piperazine-1-carbonyl)phenyl)amino)-4,5-dihydropyrazin-2-yl)phenyl)benzamidetrifluoroacetic acid Salt (2j)

To a solution of tert-butyl4-(4-((6-(3-amino-2-methylphenyl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)benzoyl)piperazine-1-carboxylate(2h, 238 mg, 0.46 mmol, 1 equiv.) in anhydrous DCM (4 mL) was addedanhydrous pyridine (56 μL, 0.68 mmol, 1.5 equiv.) and 4-tert-butylbenzoyl chloride (107 μL, 0.55 mmol, 1.2 equiv.). After stirring at roomtemperature for 1 h, the reaction mixture was concentrated to provide 2jas crude solid, which was carried onto next step directly withoutfurther purification.

Step 6.4-(tert-butyl)-N-(2-methyl-3-(4-methyl-5-oxo-6-((4-(piperazine-1-carbonyl)phenyl)amino)-4,5-dihydropyrazin-2-yl)phenyl)benzamidetrifluoroacetic acid Salt (2-1)

4-(tert-butyl)-N-(2-methyl-3-(4-methyl-5-oxo-6-((4-(piperazine-1-carbonyl)phenyl)amino)-4,5-dihydropyrazin-2-yl)phenyl)benzamide trifluoroacetic acidsalt (2j) was dissolved in anhydrous DCM (3 mL) and trifluoroacetic acid(3 mL) was added. After stirring for 2 h, the reaction mixture wasconcentrated. The resulting crude product was dissolved in DMSO andpurified using a HPLC chromatography on a reverse phase C₁₈ column toafford intermediate 2-1 as a white solid (154 mg, 0.22 mmol, 48% yieldover two steps). ¹H NMR (500 MHz, DMSO) δ 9.90 (s, 1H), 9.50 (s, 1H),8.85 (s, 2H), 8.11 (d, J=8.7 Hz, 2H), 7.95 (d, J=8.4 Hz, 2H), 7.55 (d,J=8.5 Hz, 2H), 7.42-7.34 (m, 3H), 7.33-7.27 (m, 3H), 3.67 (bs, 4H), 3.57(s, 3H), 3.17 (bs, 4H), 2.28 (s, 3H), 1.33 (s, 9H).

Example 2: Synthesis of4-(tert-butyl)-N-(3-(6-((4-(4-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetamido)ethoxy)ethoxy)ethyl)piperazine-1-carbonyl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)benzamide(I-1)

Step 1. tert-butyl(2-(2-(4-(4-((6-(3-(4-(tert-butyl)benzamido)-2-methylphenyl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)benzoyl)piperazin-1-yl)ethoxy)ethyl)carbamate(2j)

4-(tert-butyl)-N-(2-methyl-3-(4-methyl-5-oxo-6-((4-(piperazine-1-carbonyl)phenyl)amino)-4,5-dihydropyrazin-2-yl)phenyl)benzamidetrifluoroacetic acid salt (2-1, 112 mg, 0.163 mmol, 1 equiv.),tert-butyl (2-(2-(2-bromoethoxy)ethoxy)ethyl)carbamate (2i, 111 mg,0.356 mmol, 2 equiv.), and K₂CO₃ (113 mg, 0.815 mmol, 5 equiv.) weredissolved in anhydrous DMF (2 mL) and then stirred at 80° C. in a sealedvial for 8 h. The reaction mixture was cooled to room temperature andwater (3 mL) was added. The resulting mixture was extracted with EtOAc(4×10 mL). The combined organic layers were washed with H₂O (2×3 mL) andbrine (1×3 mL), dried with Na₂SO₄, filtered, and concentrated to afford2j as an oil which was carried onto the next step without furtherpurification.

Step 2.N-(3-(6-((4-(4-(2-(2-(2-aminoethoxy)ethoxy)ethyl)piperazine-1-carbonyl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4-(tert-butyl)benzamidetrifluoroacetic acid Salt (2k)

tert-butyl(2-(2-(4-(4-((6-(3-(4-(tert-butyl)benzamido)-2-methylphenyl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)benzoyl)piperazin-1-yl)ethoxy)ethyl)carbamate(2j) was dissolved in anhydrous DCM (2 mL), and trifluoroacetic acid (2mL) was added. The reaction mixture was stirred for 20 min. Theresulting solution was concentrated and purified using HPLC on a reversephase C₁₈ column to afford 2k as a white solid (16 mg, 0.02 mmol, 12%yield over two steps). ¹H NMR (500 MHz, DMSO) δ 9.91 (s, J 8.0 Hz, 1H),9.51 (s, J 18.5 Hz, 1H), 8.12 (d, J 8.7 Hz, 2H), 7.95 (d, J 8.5 Hz, 2H),7.84 (s, J 18.4 Hz, 3H), 7.58-7.51 (m, 2H), 7.43-7.33 (m, 3H), 7.33-7.23(m, 3H), 3.82-3.68 (m, 2H), 3.65-3.52 (m, 10H), 3.40-3.23 (m, 7H),3.19-3.04 (m, 2H), 3.04-2.87 (m, 2H), 2.29 (s, 3H), 1.33 (s, 9H).

Step 3.4-(tert-butyl)-N-(3-(6-((4-(4-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetamido)ethoxy)ethoxy)ethyl)piperazine-1-carbonyl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)benzamide(I-1)

To a solution ofN-(3-(6-((4-(4-(2-(2-(2-aminoethoxy)ethoxy)ethyl)piperazine-1-carbonyl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4-(tert-butyl)benzamidetrifluoroacetic acid salt (2k, 8 mg, 0.0815 mmol),(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycine (21, 40mg, 0.122 mmol, 1.5 equiv.), and diisopropylethylamine (43 μL, 0.244mmol, 3 equiv.) in anhydrous DMF (1 mL), was added 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate(50 mg, 0.130 mmol, 1.6 equiv.) and the resulting mixture was stirred atr.t. for 1 h. The reaction mixture was purified using HPLC on a reversephase C18 column followed by further purification via silica gel columnto provide I-1 as a yellow solid (9.4 mg, 0.0092 mmol, 11% yield). ¹HNMR (500 MHz, DMSO) δ 11.09 (s, 1H), 9.88 (s, 1H), 9.44 (s, 1H), 8.14(t, J=5.4 Hz, 1H), 8.07 (d, J=8.3 Hz, 2H), 7.94 (d, J=8.4 Hz, 2H), 7.56(dd, J=18.7, 8.0 Hz, 3H), 7.42-7.20 (m, 6H), 7.06 (d, J=7.0 Hz, 1H),6.94 (t, J=5.6 Hz, 1H), 6.85 (d, J=8.5 Hz, 1H), 5.07 (dd, J=12.7, 5.3Hz, 1H), 3.92 (d, J=5.5 Hz, 2H), 3.69-3.36 (m, 16H), 3.28-3.19 (m, 2H),2.89 (dd, J=21.4, 9.5 Hz, 1H), 2.56 (dd, J=26.9, 13.2 Hz, 3H), 2.41 (s,4H), 2.28 (s, 3H), 2.09-1.96 (m, 1H), 1.32 (s, 9H).

Example 3: Cell Assay and Western Blotting

K562 cells were treated with DMSO or with 200 nM, 1 μM, or 5 μM of a BTKbifunctional inhibitor compound of the disclosure for 12 hours, followedby protein lysate harvest and Western blotting analysis. As shown inFIG. 1A and FIG. 1B, cells treated with each of Compounds I-1, I-2,I1-3, I1-4, and I-5 showed BTK degradation.

MOLM14 cells were treated with DMSO or with 40 nM, 200 nM, 1 μM of a BTKbifunctional inhibitor compound of the disclosure for 4 hours, followedby protein lysate harvest and Western blotting analysis of BTK, AuroraA, and ca-tubulin levels. Cells treated with Compound I-3 showed BTKdegradation. (FIG. 2)

Western Blotting

Cells are lysed using RIPA buffer supplemented with protease inhibitorcocktail (Roche) and phosSTOP phosphatase inhibitor cocktail (Roche) onice for 15 minutes. The lysates are spun at 20,000×g for 15 minutes on4° C. and protein concentration is determined using BCA assay (Pierce).The following primary antibodies are used in this study: BTK, GADPH,tubulin and Aurora A kinase (all from Cell Signaling Technology). Blotsare imaged using fluorescence-labeled secondary antibodies (LI-COR) onthe OdysseyCLxImager (LI-COR). Quantification of band intensities isperformed using OdysseyCLx software (LI-COR).

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments and methods described herein. Such equivalents are intendedto be encompassed by the scope of the present application.

All patents, patent applications, and literature references cited hereinare hereby expressly incorporated by reference.

The invention claimed is:
 1. A bifunctional compound, which isrepresented by any one of structures I-2 to I-5:

or a stereoisomer or pharmaceutically acceptable salt thereof.
 2. Thebifunctional compound of claim 1, which is represented by structure I-3:

or a stereoisomer or pharmaceutically acceptable salt thereof.
 3. Apharmaceutical composition comprising the bifunctional compound of claim1, or a stereoisomer or pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier.